Cyclization Mode Research Articles

Selective electrophilic cyclization of ortho-carbonylarylacetylenols for the synthesis of cyclopenta[a]naphthalenol and 2-phenylnaphthalen-1-ol analogs.

This work demonstrates a new method for the synthesis of cyclopenta[a]naphthalenol and 2-phenylnaphthalen-1-ol analogs via selective cyclization. ortho-Alkynylarylkenones were employed as the common substrates that could be prepared by Sonogashira coupling between 2-haloarylacetophenone and pent-4-yn-1-ol derivatives. These precursors were used without purification to construct 2-phenylnaphthalen-1-ol intermediates by treating with (+)-CSA under heating conditions. Selective cyclization occurred when the reaction was conducted in methyl trimethylacetate solvent which predominantly produced the 2-phenylnaphthalen-1-ol product through 6-endo-dig cyclization without elimination or the formation of cyclopenta[a]naphthalenol via shutting down the 5-exo-dig mode of cyclization. Switching the acid from a Brønsted acid to Bi(OTf)3 led to smooth reactions, providing the cyclopenta[a]naphthalenol products in moderate to good yields. Moreover, we also demonstrated the utilization of 2-phenylnaphthalen-1-ol to prepare naphthoquinone, which is an important core structure of bioactive and natural product compounds.

Rational enzyme design for enabling biocatalytic Baldwin cyclization and asymmetric synthesis of chiral heterocycles

Chiral heterocyclic compounds are needed for important medicinal applications. We report an in silico strategy for the biocatalytic synthesis of chiral N- and O-heterocycles via Baldwin cyclization modes of hydroxy- and amino-substituted epoxides and oxetanes using the limonene epoxide hydrolase from Rhodococcus erythropolis. This enzyme normally catalyzes hydrolysis with formation of vicinal diols. Firstly, the required shutdown of the undesired natural water-mediated ring-opening is achieved by rational mutagenesis of the active site. In silico enzyme design is then continued with generation of the improved mutants. These variants prove to be versatile catalysts for preparing chiral N- and O-heterocycles with up to 99% conversion, and enantiomeric ratios up to 99:1. Crystal structural data and computational modeling reveal that Baldwin-type cyclizations, catalyzed by the reprogrammed enzyme, are enabled by reshaping the active-site environment that directs the distal RHN and HO-substituents to be intramolecular nucleophiles.

Unexpected Stereoselective Access to 2‐Aminooxazolines from Propargyl Ureas by Silver Salts under Mild Conditions

AbstractPropargyl ureas can lead to a range of possible heterocyclic compounds, mainly depending on the employed catalyst. Silver salts are known to promote the N‐5‐exo‐dig cyclization mode to imidazolidinone derivatives. Conversely, a versatile and stereoselective O‐5‐exo‐dig cyclization of propargyl ureas to 2‐aminooxazolines by Ag(I) catalysis is here disclosed. Good to excellent yields and complete stereoselectivity of the external double bond have been achieved under milder reaction conditions (50–60 °C). A one‐pot protocol starting from the corresponding propargylic amines and isocyanates has been developed as well. N,N’‐Dipropargyl ureas underwent a uncommon O‐5‐exo‐dig/N‐5‐endo‐dig double cyclization sequence. Finally, insights into the tautomeric equilibrium of 2‐aminooxazoles and on their relative reactivity are provided.magnified image

Photoluminescence mechanisms of red-emissive carbon dots derived from non-conjugated molecules

Red-emissive carbon dots (R-CDs) have been widely studied because of their potential application in tissue imaging and optoelectronic devices. At present, most R-CDs are synthesized by using aromatic precursors, but the synthesis of R-CDs from non-aromatic precursors is challenging, and the emission mechanism remains unclear. Herein, different R-CDs were rationally synthesized using citric acid (CA), a prototype non-aromatic precursor, with the assistance of ammonia. Their structural evolution and optical mechanism were investigated. The addition of NH3·H2O played a key role in the synthesis of CA-based R-CDs, which shifted the emission wavelength of CA-based CDs from 423 to 667 nm. Mass spectrometry (MS) analysis indicated that the amino groups served as N dopants and promoted the formation of localized conjugated domains through an intermolecular amide ring, thereby inducing a significant emission redshift. The red-emissive mechanism of CDs was further confirmed by control experiments using other CA-like molecules (e.g., aconitic acid, tartaric acid, aspartic acid, malic acid, and maleic acid) as precursors. MS, nuclear magnetic resonance characterization, and computational modeling revealed that the main carbon chain length of CA-like precursors tailored the cyclization mode, leading to hexatomic, pentatomic, unstable three/four-membered ring systems or cyclization failure. Among these systems, the hexatomic ring led to the largest emission redshift (244 nm, known for CA-based CDs). This work determined the origin of red emission in CA-based CDs, which would guide research on the controlled synthesis of R-CDs from other non-aromatic precursors.

The xanthate route to six-membered carbocycles

Convergent routes to various six-membered carbocyclic architectures exploiting the unique radical chemistry of xanthates are described in this brief review. Three approaches are discussed. The first is the modification of existing cyclohexane building blocks, namely, cyclohexanones, cyclohexenones and cyclohexenes. The second deals with the construction of six-membered carbocycles by associating the chemistry of xanthates with classical ionic reactions, especially the Robinson annulation, the Michael addition and the Horner–Wadsworth–Emmons condensation. Finally, the third route is the formation of six-membered rings by direct six- exo and, but more rarely, six- endo cyclisation modes. Many of the complex structures presented herein would be tedious to obtain by more traditional methods.

The selective regulation of borylation site based on one-shot electrophilic C–H borylation reaction, achieving highly efficient narrowband organic light-emitting diodes

The electrophilic borylation site of borylation reaction can be selectively controlled by varying the steric hindrance and electron-donating ability of the substrate substituent. The device based on the synthesized compound exhibits EQE of 21.6% with FWHM of 28 nm and CIE coordinates of (0.135, 0.094). The work provides an effective way for the development of high-performance MR-TADF emitter. • The electrophilic borylation site of one-shot electrophilic C–H borylation reaction can be selectively controlled. • New compounds tDPAC-BN and tDMAC-BN exhibited high PLQYs, narrow FWHMs, and satisfactory TADF properties. • The device based on tDPAC-BN achieved EQE of 21.6% with FWHM of 28 nm and CIE coordinates of (0.135, 0.094). Developing novel thermally activated delayed fluorescence (TADF) materials with a small full-width at half-maximum (FWHM) is very important for the fabrication of wide gamut and high-resolution displays of organic light-emitting diodes (OLEDs). In this work, we report two blue TADF emitters (tDPAC-BN and tDMAC-BN) with narrow FWHM based on a one-shot electrophilic C–H borylation reaction by selecting acridan-containing arylamine derivatives as the starting materials of borylation. The rigid skeleton structure significantly reduces vibrational motion, endowing tDPAC-BN and tDMAC-BN with high PLQYs (94.4% and 89.7%) and narrow FWHMs (19 nm and 26 nm in toluene). The electroluminescent devices employing tDPAC-BN and tDMAC-BN as emitters exhibit external quantum efficiency (EQE) of 21.6% and 22.3%, and CIE coordinates of (0.135, 0.094) and (0.116, 0.186), respectively. More importantly, we found the electrophilic borylation site of borylation reaction can be controlled by varying the steric hindrance effect and electron-donating ability of the substrate substituent. The different HOMO distribution originated from the differences in the substrate substituent accounts for different cyclization mode for tDPAC-BN and tDMAC-BN. Therefore, the work provides a useful strategy for broadening the range of high-performance TADF materials with narrow FWHM.

Stereochemistry of the Benzylidene γ-Butyrolactone Dictates the Reductive Heck Cyclization Mode in the Asymmetric Synthesis of Aryltetralin Lignans: A Detailed Experimental and Theoretical Study.

The reductive Heck cyclization of nonracemic benzylidene γ-butyrolactone is studied toward the asymmetric synthesis of aryltetralin lignans, where the stereochemistry of the benzylidene lactone is found to control the mode of cyclization. The Z-isomer undergoes mostly 6-endo-cyclization and provides the desired (-)-isopodophyllotoxin along with a minor amount of 5-exo-cyclized product, but the E-isomer goes through exclusively 5-exo-cyclization, leading to the undesired dihydroindenolactone compound instead of (-)-podophyllotoxin. The experimental results are well-supported by the DFT studies.

Pathways to fluorescence via restriction of intramolecular motion in substituted tetraphenylethylenes

Functionalization is used to restrict the torsional, excited-state proton transfer and cyclization modes in UV-excited tetraphenylethylenes.

Discovery of branching meroterpenoid biosynthetic pathways in Aspergillus insuetus: involvement of two terpene cyclases with distinct cyclization modes.

The aromatic polyketide 3,5-dimethylorsellinic acid (DMOA) serves as a precursor for many fungal meroterpenoids. A large portion of DMOA-derived meroterpenoids are biosynthesized via the cyclization of (6R,10′R)-epoxyfarnesyl-DMOA methyl ester (1). Theoretically, although 1 can be cyclized into many products, only three cyclization modes have been reported. Here, we discovered a meroterpenoid biosynthetic gene cluster in Aspergillus insuetus CBS 107.25, which encodes the biosynthetic enzymes for 1 along with a terpene cyclase that is phylogenetically distantly related to the other characterized cyclases of 1. Intriguingly, InsA7, the terpene cyclase, folds 1 in a pre-boat-chair conformation, generating a new meroterpenoid species with an axially oriented hydroxy group at C3. The A. insuetus strain also harbors an additional gene cluster encoding another cyclase of 1. The second terpene cyclase–InsB2–also synthesizes a new cyclized product of 1, thereby leading to diverging of the biosynthetic pathway in the fungus. Finally, we characterized the tailoring enzymes encoded by the two clusters, collectively obtained 17 new meroterpenoids, and successfully proposed biosynthetic routes leading to apparent end products of both pathways.

Divergent Synthesis of Skeletally Distinct Arboridinine and Arborisidine.

A divergent synthesis of skeletally distinct arboridinine and arborisidine was achieved. The central divergent strategy was inspired by the divergent biosynthetic cyclization mode of arboridinine and arborisidine and their hidden topological connection. The branch point was reached through a Michael and Mannich cascade process. A site-selective intramolecular Mannich reaction was developed to construct the tetracyclic core of arboridinine, while a site-selective intramolecular α-amination of ketone was used to access the tetracyclic core of arborisidine. A strategic Peterson olefination through intramolecular nucleophile delivery was able to set up the exocyclic olefin of arboridinine.

Regiodivergent Carbene/Alkyne Metathesis in Chromium-Mediated Coupling and Cyclization with 1,6-Enynes

Abstract Regiodivergent carbene/alkyne metathesis for the selective synthesis of 2-alkylidenebicyclo[4.1.0]heptanes and 1-alkenylbicyclo[3.1.0]hexanes from common 1,6-enynes precursors was demonstrated. The cyclization mode could be switched by simple addition of diamine ligands to control the relative orientation of the approaching chromium Schrock carbene equivalents generated in situ from gem-dichromiomethanes toward triple bonds.

Using Terpene Synthase Plasticity in Catalysis: On the Enzymatic Conversion of Synthetic Farnesyl Diphosphate Analogues.

Four synthetic farnesyl diphosphate analogues were enzymatically converted with three bacterial sesquiterpene synthases, including β‐himachalene synthase (HcS) and (Z)‐γ‐bisabolene synthase (BbS) from Cryptosporangium arvum, and germacrene A synthase (SmTS6) from Streptomyces mobaraensis. These enzyme reactions not only yielded several previously unknown compounds, showing that this approach opened the door to a new chemical space, but substrates with blocked or altered reactivities also gave interesting insights into the cyclisation mechanisms and the potential to catalyse reactions with different initial cyclisation modes.

Syntheses of thiophene appended N-confused phlorin isomers

A doubly confused thiapentapyrrane NSP-5 was synthesized by acid-catalysed condensation. Subsequent oxidation with DDQ did not afford the expected thiasapphyrin-like product. Instead, two tetrapyrrolic macrocycles, i.e. neo-N-confused phlorin (1) and N-confused phlorin-II (2) were obtained in the yields of 14% and 18%, respectively. The compounds were characterized by NMR, HRMS, and X-ray diffraction analyses. Single crystal structures clearly reveal that the thienyl units are not embedded into the macrocycles, but appended as meso-substituents, and the C[Formula: see text]-N and C[Formula: see text]-C[Formula: see text] cyclization modes can be clearly revealed by the crystal structures of 1 and 2, respectively. The observation that the thienyl unit is not involved in oxidative cyclization may be related to the relatively low reactivity of the thiophene moiety compared with the more electron-rich pyrrole unit. These results indicate that oxidative cyclization of linear thiaoligopyrranes containing terminal thiophene units may be developed as an effective approach for synthesizing nonconjugated macrocycles like phlorin analogues.

Beyond the Isoprene Pattern: Bifunctional Polyene Cyclizations.

Polyene cyclizations are capable of producing molecular complexity in a single step. While classical systems are limited to simple alkyl substitution patterns only, bifunctional polyenes take advantage of the unique reactivity of higher‐functionalized alkenes. Here, we highlight the potential of these variants for the synthesis of structurally complex polycycles involving unprecedented termination steps. We also want to provide a stimulus for the development of novel modes of cyclization that involve bifunctional units to enable efficient synthesis of yet inaccessible natural products.

Total Synthesis, Structure Revision, and Neuroprotective Effect of Hericenones C-H and Their Derivatives.

The first total syntheses of hericenones C-H and "putative 3-hydroxyhericenone F" were achieved. Highlights of the synthesis include the straightforward construction of the resorcinol core and geranyl side chain, assembly of the natural product skeleton by sequential O-geranylation and a clay/zeolite-mediated O → C rearrangement reaction, and a biomimetic cyclization to form a variety of bicyclic natural hericenones and their congeners. The structure of the "putative 3-hydroxyhericenone F" was revised as the 5-exo cyclization product (named: hericenone Z) of epoxyhericenone C through in-depth analyses of the cyclization modes in addition to NMR spectroscopic studies. To gain insights into the biological functions of geranyl-resorcinols in Hericium erinaceus, potential neuroprotective effects against endoplasmic reticulum (ER) stress-dependent cell death were evaluated systematically to clarify a fundamental structure-activity relationship. Among the compounds assayed, the linoleate-containing hericenone analogue, i.e., the regioisomer of hericene D, was found to possess the most potent neuroprotective effect against tunicamycin and thapsigargin-induced ER stress-dependent cell death.

Pressure-induced annulative orifice closure of a cage-opened C60 derivative.

A cage-opened C60 derivative was found to undergo an unusual annulative orifice-closure reaction under high-pressure conditions, in which the orifice size changed from a 16- to a 13-membered ring. The structure was different from that obtained by the reaction at 1 atm. The theoretical calculations suggested that the formation of the former one is thermodynamically favored.

Construction of Medium-Sized Rings by Gold Catalysis.

Compounds having cyclic molecular frameworks are highly regarded for their abundance and diverse utilities. In particular, medium-sized carbocycles and heterocycles exist in a broad spectrum of natural products, bioactive therapeutics, and medicinally significant synthetic molecules. Metal-mediated methods have been developed for the preparation of compounds containing a medium-sized ring (MSR) through cyclization of different classes of substrates and acyclic precursors. This review focuses on the methodologies for construction of MSRs via gold catalysis. Given the challenges in enabling the assembly of different ring sizes, we present here accounts on Au-mediated cyclization giving notable 7-membered and medium-sized (8-11-membered ring) structures. Emphasis on the pathway and mode of cyclization and the selection of precursors ranging from structurally biased compounds were outlined. Reactivity patterns and the choice of efficient Au catalysts for controlling reaction performance and selectivity in addition to mechanistic attributes are examined.

Insights into the mechanism and regiochemistry of the 1,3-dipolar cycloaddition reaction between benzaldehyde and diazomethane

The 1,3-dipolar cycloaddition reaction of benzaldehyde with diazomethane is investigated, in gas phase and in diverse polar solvents, using the molecular electron density theory through density functional theory calculations at the B3LYP(+D3)/6-31G(d) level. Analysis of the reaction pathway reveals that this reaction takes place along a concerted but asynchronous mechanism. Computations show that the acetophenone product is kinetically and thermodynamically more favored than 2-phenylacetaldehyde product in agreement with experimental outcomes. The favored cyclization mode and the observed regioselectivity of this cycloaddition are rationalized by both activation energy calculations, frontier molecular orbital analysis and reactivity indices. Also, polar solvents effect favors the reaction. Furthermore, we performed electron localization function (ELF) topological analysis. The ELF topological analysis of diazomethane indicates that this reactant presents an allenic pseudoradical electronic structure.

Reductive Condensation of a Nitro Group with Carboxylic Acids Promoted by Phosphorus(III) Compounds: A Short Route to 5H-Dibenzo[b,e][1,4]diazepin-11(10H)-ones

Tributyl- or triphenylphosphine promotes a one-pot, three-step method for the synthesis of differently substituted dibenzodiazepinones from N-aryl-2-nitroanilines. Pyridine analogues and the corresponding thiazepinones can also be formed using this method. The process involves deoxygenation of the nitro group, then formation of an iminophosphorane intermediate and its intramolecular condensation with a carboxyl group placed in the N-aryl group. The role of the carboxyl group in the formation of the iminophosphorane and the mode of cyclization are discussed.

Bifunctionalized allenes. Part XXIV. Competitive electrophilic cyclization of 5-(dimethoxyphosphoryl)-alka-3,4-dienoates leading to 2,5-dihydro-1, 2-oxaphospholes and 5,6-dihydro-2H-pyranes

We report herein a study on the competitive electrophilic cyclization of 5-(dimethoxyphosphoryl)-alka-3,4-dienoates involving 5-endo-trig and 6-endo-trig mode cyclizations. Reaction with electrophiles produces mixtures of the 2-(2-oxo-2,5-dihydro-1,2-oxaphosphol-5-yl)-alkanoates and (6-oxo-5,6-dihydro-2H-pyran-2-yl)-phosphonates by competitive electrophilic cyclization due to the participation of the neighboring phosphonate and carboxylate groups.