Cyclobutane Adducts Research Articles

2+2] Photodimerization of Stilbazoles Promoted by Oxalic Acid in Suspension

In this study we reported on a very simple technique to perform efficiently photodimerization of some vinylpyridines. By irradiating a stirred mixture of several stilbazoles with solid oxalic acid dihydrate dispersed in a non-polar ( e.g. cyclohexane) or moderately polar (benzene, dichloromethane, dioxane) solvent, the corresponding dimeric cyclobutane adducts were obtained in high yields with excellent of regio- and stereo- selectivities. The strategy could also be applied successfully to oily, waxy or even insoluble stilbazoles. Moreover, the oxalic acid loading could be lowered to sub-stoichiometric amounts. When further optimizations were needed, our strategy was found to be highly flexible to identify other oligocarboxylic acids as alternative additive to improve or even overturn regioselectivity. Oxalic acid and other oligocarboxylic acids were found to be capable of orienting more than fifty stilbazoles toward photodimerization under these conditions.

Pressure, temperature, and solvent effects on the rates of reactions of 3,4-dihydro-2H-pyran with tetracyanoethylene and 4-phenyl-1,2,4-triazoline-3,5-dione

The effects of high hydrostatic pressure, temperature, and solvent on the rates of reactions of tetracyanoethylene (1) and 4-phenyl-1,2,4-triazoline-3,5-dione (2) with 3,4-dihydro-2Hpyran ( 3) were studied. The X-ray diffraction analysis showed that the reaction of compounds 1 and 3 occurs with the formation of the cyclobutane adduct. The reaction is characterized by enhanced entropy and activation volume, as well as a high influence of the solvent polarity (ET) on the rate (R = 0.975). The course of the reaction 2 + 3 differs sharply from the reaction 1 + 3 by the values of entropy and activation volume, the absence of the effect of the solvent polarity on the rate, and the presence of mono-, di-, and trimeric reaction products. Possible routes of these reactions are considered.

A Bis-benzopyrroloisoquinoline Alkaloid Incorporating a Cyclobutane Core and a Chlorophenanthroindolizidine Alkaloid with Cytotoxic Activity from Ficus fistulosa var. tengerensis.

Tengerensine (1), isolated as a racemate and constituted from a pair of bis-benzopyrroloisoquinoline enantiomers, and tengechlorenine (2), purified as a scalemic mixture and constituted from a pair of chlorinated phenanthroindolizidine enantiomers, were isolated from the leaves of Ficus fistulosa var. tengerensis, along with three other known alkaloids. The structures of 1 and 2 were determined by spectroscopic data interpretation and X-ray diffraction analysis. The enantiomers of 1 were separated by chiral-phase HPLC, and the absolute configurations of (+)-1 and (-)-1 were established via experimental and calculated ECD data. Compound 1 is notable in being a rare unsymmetrical cyclobutane adduct and is the first example of a dimeric benzopyrroloisoquinoline alkaloid, while compound 2 represents the first naturally occurring halogenated phenanthroindolizidine alkaloid. Compound (+)-1 displayed a selective in vitro cytotoxic effect against MDA-MB-468 cells (IC50 7.4 μM), while compound 2 showed pronounced in vitro cytotoxic activity against all three breast cancer cell lines tested (MDA-MB-468, MDA-MB-231, and MCF7; IC50 values of 0.038-0.91 μM).

Reinvestigation of dimerization of Z-N-alkylarylmethylideneindoxyls upon exposure to UV-vis radiation

N-Alkyl-2-arylmethylideneindoxyls upon exposure to UV or visible light undergo dimerization not to cyclobutane adducts as it has been reported earlier, but to spiropyrano[3,2-b]-pseudoindoxyls with a spiropseudoindoxyl fragment characteristic of many natural alkaloids. The structure of spiropyranopseudoindoxyls was established by NMR spectroscopy and X-ray crystallography.

Photochemical transformation of a 1,2-dihydropyridin-3-one: an original tandem retro-[4+2]/[2+2] cycloaddition process

The UV irradiation of N-benzyl-2-phenyl-1,2-dihydropyridin-3-one furnished trans-1-benzyl-4-phenyl-3-vinylazetidin-2-one, a structural isomer, as the main product. A novel tandem mechanism involving a [4+2] photocycloreversion followed by a Staudinger cycloaddition reaction is proposed, and is supported with the trapping of the purported vinylketene intermediate by other imines. This process predominates in the presence of ethylene, precluding the formation of an intermolecular [2+2] cyclobutane adduct.

Synthesis of cyclobutane lignans via an organic single electron oxidant–electron relay system

A direct method to synthesize lignan cyclobutanes and analogs via photoinduced electron transfer is presented. A variety of oxygenated alkenes are employed to furnish terminal or substituted cyclobutane adducts with complete regiocontrol, yielding cycloadducts with trans stereochemistry. Key to minimizing competing cycloreversion is the inclusion of an aromatic electron relay (ER). This method has been adapted to the synthesis of the natural products magnosalin and pellucidin A.

Ab initio Calculation for Photochemistry of Psoralen Derivatives

Psoralens (Ps) are a class of heterocyclic aromatic compounds that have been extensively utilized in the photochemotherapy of skin disorders such as psoriasis and vitiligo, cutaneous T-cell lymphoma. On exposure to ultraviolet light, especially in the range of 320-400 nm, psoralens form chemical crosslinks to the DNA bases in the three steps. The first step is intercalation of psoralen between to adjacent base-pairs. The second step is formation of monoadduct; that is one psoralen molecule photo-react with one strand of DNA. The third step is the cross-linking of the same psoralen molecule to the other strand of DNA, thus covalently linking the two strand of a double stranded DNA. Psoralens have two photochemical reaction sites, 3,4pyrone double bond and 12,13-furan double bond, both of which are engaged in cross-linking of DNA bases. The formation of interstrand cross-linking through C4-cycloaddition of 3,4and 12,13-double bonds to the 5,6-double bond of the pyrimidine bases, especially thymine, in DNA has been correlated with the biological effects of photoexcited psoralens. Binding of Ps to DNA is generally the consequence of two successive events (1) intercalation into DNA between the base pairs; and (2) photocycloaddition reaction of 3,4Pyrone double bond and/or 12,13-furan double bond with 5,6-double bond of thymine. Although several photoproducts of purine bases from direct and photosensitized irradiation of purines are known, the photoaddition reaction between the excited psoralens and purine bases are not well understood. In the present paper, we report that the formation of interstrand cross-linking through C4-cycloaddition of 3,4and 12,13-double bonds to the 5,6-double bond of the pyrimidine bases, especially thymine, in DNA is calculated by the ab initio method. The molecular geometries are optimized at HF levels of theory with the 6-31G basis set by using the Gaussian 03 program. The 6-31G optimizations of the final structures are done to include the effect of electron correlation and the basis set with polarization function. The photosensitization activity of psoralens is generally correlated to their photoreactivity with pyrimidine bases in DNA. The cross-linkage is caused by the formation of cyclobutane adducts, which are produced by photoreactions of the psoralen 3,4-pyrone and 12,13-furan double bonds to two pyrimidine bases. The association energies for photocycloadduct (ΔE) are obtained by subtracting the sum of the energies of the 5MOP and two thymine from the energy of the full optimized photocycloadduct.

Photocycloaddition of Conjugated Cyclohex‐2‐enones to 2,3‐Dimethylbuta‐1,3‐diene

AbstractOn irradiation, in the presence of 2,3‐dimethylbuta‐1,3‐diene, naphthalen‐2‐ones 1 are quantitatively and regioselectively converted to mixtures of diastereoisomeric cyclobutane adducts 3 and 4, whereas, under these conditions, 3‐(alk‐1‐ynyl)cyclohex‐2‐enones 5 give only one cyclobutane adduct 6 regio‐ and diastereoselectively. In contrast, 3‐(alk‐1‐ynyl)‐2‐methylcyclohex‐2‐enones 10 undergo [2+2]‐cycloaddition to the same diene exclusively at the C≡C bond to afford hitherto unknown 3‐cyclobutenylcyclohex‐2‐enones 11.

UVB photolysis of hydrocortisone 21-acetate

Hydrocortisone 21-acetate (HCA) in methanol solution undergoes photodegradation under UVB light, as monitored by HPLC. Five main photoproducts have been isolated and characterized by means of NMR and mass spectroscopy. One of them derives from a Norrish I photoreaction which cleaves the C17–C20 bond of the steroid yielding the andro-derivative, a second product comes from a Yang-type photorearrangement which links C18 to C20 yielding a cyclobutane adduct. The former photoproduct, in turn, undergoes further photolysis giving rise to various photoproducts, of which three have been characterized. The first is a stereoisomer of the andro-derivative, the others arise from the opening of the five-membered ring. HCA also proved photounstable in the solid state and in a commercial formulation for topical use, thus confirming the requirements of the Pharmacopeias for light protection of this drug. Indeed, experiments on LPS-stimulated THP-1 cells demonstrated the loss of anti-inflammatory activity when HCA was UVB-photodegraded. The radical mechanism involved in HCA photolysis seems also responsible for the in vitro photohemolytic effect and lipid peroxidation induced by HCA in combination with UVB light.

Photochemical behaviour of 5-formyl and 5-acetyl uracils in the presence of ethene

Atypically for uracils, 5-formyl and 5-acetyl uracils react photochemically with excess ethene to produce non-acylated cyclobutane adducts whose formation can be explained by a novel, tandem [2+2] cycloaddition/Norrish-I α-cleavage process.

Modeling Thymine Photodimerizations in DNA: Mechanism and Correlation Diagrams

The basic mechanistic traits of the main photochemical reactions in DNA, the formation of the cyclobutane and oxetane thymine dimerization adducts, are established with the help of CASSCF and CASPT2 calculations for a gas-phase model of two stacked thymines. Both reactions go through conical intersections between the ground and the excited state that are connected through minimum energy paths to the corresponding products. This explains the ultrafast formation of the cyclobutane adduct detected experimentally, and it suggests that the oxetane formation also occurs on that time scale. Moreover, the states responsible for the photoproduct formation correlate with two high-lying states of the pair in its ideal B-DNA conformation. These states are different from the delocalized states resulting from coupling of the localized ones, which suggests that the origin of the reactive electronic states lies in the pi stacking. Formation of the photoproducts requires population of these states, by direct excitation of favorable conformations, or preceded by a localized excitation.

Synthesis and spectroscopic and structural studies of cross-conjugated dienones derived from cyclic ketones and aromatic aldehydes

Cross-conjugated dienones were synthesized by the reactions of cyclic ketones with two equivalents of aromatic aldehydes under basic conditions. An NMR spectroscopic study and X-ray diffraction analysis demonstrated that all reaction products are formed as E,E isomers. Spontaneous photochemical trans-cis isomerization of cross-conjugated dienones under the scattered light in solution was observed for the first time. The degree of isomerization depends mainly on the nature of the central fragment of the dienone molecule. The previously unknown product of photochemical [2+2]-cycloaddition of 2,5-bis[(E)-(3-pyridyl)methylidene]cyclopentanone was synthesized and characterized by spectroscopic methods and X-ray diffraction. Under the conditions used, only one isomer of the cyclobutane adduct was obtained.

Photocycloaddition of 5-bromouracil to uracil in a dinucleotide model compound

The photochemical reactivity of 5-bromouracil towards uracil in a dinucleotide model compound 1 has been examined. The formation of a cyclobutane adduct 2 as a major product (>90%), without debromination of the 5-bromouracil moiety was observed upon irradiation of 1 with near UV light (λ >300 nm) under both anaerobic and aerobic conditions. Upon heating, 2 undergoes cyclobutane ring cleavage with concomitant hydrolysis to form 5-hydroxyuracil analogue 3 as a major product.

Spectroscopic detection of photoproducts in lecithin model system after 8-methoxypsoralen plus UV-A treatment

Photoreactions of 8-methoxypsoralen (8-MOP) in the presence of synthetic lecithins esterified at the β-position with linoleic/oleic and γ-palmitic acid (PCd2/d1pal) have been studied. Following UV-A (320–400 nm) irradiation, the photoproducts separated by thin-layer chromatography are analysed by UV absorption spectroscopy, nuclear magnetic resonance and mass spectroscopy. The new isolated products are lecithin double cyclobutane adducts, PC–(8-MOP) 2, fatty acid–8-MOP split adducts from phosphatidylcholine and lecithin adducts with photo-oxidized 8-MOP. The photolysis performed in the presence of 8-MOP is related to the previously reported lecithin cyclobutane adducts with psoralen. A hypothetical scheme of lecithin photolysis under PUVA (psoralen+UV-A) treatment is proposed. We suggest that photolysis of lecithin may have a significant role in the chain of reactions triggered in cell membrane submitted to PUVA treatment.

Unusual [2+2] Photocycloaddition between Tryptamine and 3-Nitrocinnamic Acid in the Solid State

Abstract A crystalline salt of tryptamine with trans-3-nitrocinnamic acid underwent cross photocycloaddition, leading to a cyclobutane adduct 1. Their solid mixture failed to give 1. This is the first [2+2] photocycloaddition of alkene to “N-unsubstituted” indoles.

Photocycloaddition of arylethenes to 2-substituted-1,4-naphthoquinones and reactions of the cyclobutane adduct isomers

The photoreactions of 2-chloro-, 2-bromo-, 2,3-dichloro- and 2,3-bromo-1,4-naphthoquinones with arylethenes are dependent on the addend structure. Cyclobutane adducts are formed from styrene, 1,1-diphenylethene undergoes photosubstitution to give photolabile 1,1-diphenyl-1,3-diene derivatives, and spiro-oxetanes are the main products with trans-stilbene. 2-Acetoxy-1,4-naphthoquinone undergoes efficient (2π + 2π) photocycloaddition to isobutene, styrene and 1,1-diphenylethene but trans-stilbene yields the spiro-oxetane, 3′,4′-diphenyl-3-acetoxyspiro[naphthalene-1,2′-oxetan]-4(1H)-one, 34 regiospecifically. The isobutene adduct, 1,1-dimethyl-8a-acetoxy-1,2,2a,8a-tetradihydrocyclobuta[b]naphthalene-3,8-dione, 27 reacts readily with potassium tert-butoxide to yield 1,1-dimethyl-1,2-dihydrocyclobuta[b]naphthalene-3,8-dione 11 and is hydrolysed under acid conditions to the corresponding alcohol. In contrast the acetoxycyclobutanes from styrene and 1,1-diphenylethene give only the quinone dimers on base treatment, and under the acid conditions of its formation, the alcohol from the styrene adducts rearranges to 1-hydroxy-11-exo-phenyltricyclo[7.2.1.0]dodeca-2,4,6-triene-8,12-dione 39 while the adduct from the latter arylethene undergoes formal loss of hydrogen to give the red photolabile 3-(2′,2′-diphenylethenyl)-2-hydroxy-1,4-naphthoquinone 42.

Urocanic Acid Photochemistry and Photobiology

Urocanic acid (2-propenoic acid, 3-[ lH-imidazol-4(5)-yl], UA)? is one of the smallest molecules to have stimulated global interest among biologists, environmentalists, photochemists, photobiologists, medicinal chemists and immunologists. Its history can be traced back more than a century to when it was first found in the urine of dogs (1). Interest in the molecule remained dormant until the middle of the century but rekindled in the late 1940s when it was detected in animal skin and sweat. This led to the proposal that UA acts as a natural sunscreen, possibly as a specific photoprotecting agent for DNA because of the overlap of the UA and DNA absorption spectra (2). Since 1983 there has been an explosive growth in UA research, primarily as a consequence of the proposal by De Fabo and Noonan (3) that the cis photoisomer (cUA) of trans-UA (tUA) could be responsible for the phenomenon of photoimmunosuppression. In a recent literature survey we found that about 25 research papers have appeared every year over the last decade involving UA. Several comprehensive reviews of the molecule's photobiology, photochemistry and photophysics have appeared (4-

Light-induced [2 + 2] Cycloaddition of 6-Methoxy-2-naphthonitrile to 2-Chloroacrylonitrile

6-Methoxy-2-naphthonitrile undergoes photocycloaddition to 2-chloroacrylonitrile to give [2 + 2] cyclobutane adducts (1a and 1b), the structure of one of which (1a) has been unambiguously confirmed by an X-ray structural analysis.

Ring-opening polymerization of the cyclobutane adduct of tetracyanoethylene and ethyl vinyl ether by the initiating system vinyl ether-acetic acid adduct/zinc iodide. Synthesis of a molecular weight-controlled alternating copolymer of the two olefins

Ring-opening polymerization of the cyclobutane adduct (1) of tetracyanoethylene (TCNE) and ethyl vinyl ether (EVE) was carried out with protonic acid/Lewis acid or EVE-acetic acid adduct (2)/ZnI2 as initiating systems in CH3NO2 at ambient temperature. Poly1s with narrow molecular weight distribution (MWD) were obtained with the systems acetic acid(AcOH)/ZnI2 or 2/ZnI2. In the polymerization with 2/ZnI2, the number-average molecular weight (M̄n) of the polymers decreases with increasing amount of 2/ZnI2, and increases in direct proportion to the monomer conversion. Furthermore, M̄n increases on addition of a fresh feed of monomer at the end of the first-stage polymerization. The MWD remains narrow throughout the reaction. On the basis of the reaction of 1 with an equimolar amount of 2 in the presence of ZnI2 and the diene 5 as a by-product formed by elimination of hydrogen cyanide from 1 in the polymerization, it was proposed that ZnI2 activates both the CH-OAc terminal groups of the growing polymer chain and monomer 1.

Ring-opening polymerization of the cyclobutane adduct of tetracyanoethylene and ethyl vinyl ether by the initiating system vinyl ether-acetic acid adduct/zinc iodide. Synthesis of a molecular weight-controlled alternating copolymer of the two olefins

Ring-opening polymerization of the cyclobutane adduct (1) of tetracyanoethylene (TCNE) and ethyl vinyl ether (EVE) was carried out with protonic acid/Lewis acid or EVE-acetic acid adduct (2)/ZnI2 as initiating systems in CH3NO2 at ambient temperature. Poly1s with narrow molecular weight distribution (MWD) were obtained with the systems acetic acid(AcOH)/ZnI2 or 2/ZnI2. In the polymerization with 2/ZnI2, the number-average molecular weight (M̄n) of the polymers decreases with increasing amount of 2/ZnI2, and increases in direct proportion to the monomer conversion. Furthermore, M̄n increases on addition of a fresh feed of monomer at the end of the first-stage polymerization. The MWD remains narrow throughout the reaction. On the basis of the reaction of 1 with an equimolar amount of 2 in the presence of ZnI2 and the diene 5 as a by-product formed by elimination of hydrogen cyanide from 1 in the polymerization, it was proposed that ZnI2 activates both the CH-OAc terminal groups of the growing polymer chain and monomer 1.