Applications of Norrish type I and II reactions in the total synthesis of natural products: a review.

Natural products and their analogue have played a key role in the drug discovery and development process. In the laboratory, the total synthesis of secondary metabolites is very useful in ascertaining the hypothetical complex structure of molecules of natural origin. Total synthesis of natural products using Norrish type I and II reactions as a crucial step has been explored in this overview. Norrish reactions are important photo-induced transformations of carbonyl compounds in organic synthetic chemistry and are connected in numerous industrially and biologically relevant procedures and the processing of carbonyl compounds in the atmosphere. The present review tries to focus on the brilliant applications of Norrish type I and II photochemical reactions as a key step in the total synthesis of natural products and highlights on natural sources, structures, and biological activities of the promising natural products for the first time elegantly.

Citral Photodegradation in Solution: Highlighting of a Radical Pathway in Parallel to Cyclization Pathway.

Citral, a lemon flavor molecule often used in the beverage and fragrance industry, is known to be unstable under light irradiation. Its deterioration is considered to be an important issue for the stabilization of lemon-flavored drinks. The aim of this study is to understand the degradation mechanisms of citral under light irradiation with the variation of three parameters: the solvent (citrate buffer solution at pH 3 vs ethanol), the atmosphere (air vs N2), and the concentration of citral. The photodegradation has been studied using UV-visible spectroscopy after photolysis, nuclear magnetic resonance spectrometry, and electron spin resonance spectroscopy. To extend the investigation, molecular orbitals and bond dissociation energies have also been calculated. They give an insight into the light absorption properties and the possible cleavage of citral molecular bonds. In addition, UV-light absorption and radical scavenging activities of two additives, potassium sorbate and ascorbic acid, have been studied for the inhibition of the citral photodecomposition by UV-light irradiation. Both theoretical and experimental results highlight a new degradation pathway involving free-radical intermediates in parallel to the already reported cyclization one, which could be prevented by the addition of stabilizers such as ascorbic acid or sorbate.

A desymmetrization-based approach to morphinans: application in the total synthesis of oxycodone.

Here we report a total synthesis of the pharmacologically significant morphinan alkaloid, oxycodone. The centerpiece of the developed strategy features the first application of the Rovis desymmetrization of peroxyquinol in target-oriented total synthesis to access an optically active phenanthrene framework shared by the morphinans. A Stork-Ueno radical cyclization under photoredox conditions installed the all-carbon quaternary stereocenter, and a late-stage reductive detosylation with concomitant piperidine formation secured the core structure of the target molecule.

Photochemical Activation of Enediyne Warheads: A Potential Tool for Targeted Antitumor Therapy.

Spatial and temporal control over DNA cleavage by photoactivated enediynes can be complemented by additional factors such as the release of internal strain, chelation, pH changes, intramolecular H-bonds, and substituent effects. This review presents design and reactivity of photoactivated enediynes/enynes and analyses the chemical, biological, and photophysical challenges in their applications.

Synthesis of carbonylated heteroaromatic compounds via visible-light-driven intramolecular decarboxylative cyclization of o-alkynylated carboxylic acids.

An efficient strategy for the easy access to carbonylated heteroaromatic compounds has been developed via a visible-light-promoted intramolecular decarboxylative cyclization reaction of o-alkynylated carboxylic acids. This method is characterized by its benign conditions and the tolerance to a wide range of functionalities.

Visible light induced radical cyclization of o-iodophenylacrylamides: a concise synthesis of indolin-2-one.

A [Ir(ppy)2(dtb-bpy)]PF6-catalyzed intramolecular radical cyclization of o-iodophenylacrylamides affording indolin-2-ones in moderate to excellent yields via 5-exo-trig radical cyclization under visible light is presented. This method provides new access to the synthesis of indolin-2-ones under mild reaction conditions.

Approaching two-dimensional copolymers: photoirradiation of anthracene- and diaza-anthracene-bearing monomers in Langmuir monolayers.

By using structurally similar amphiphilic monomers, it is shown that compressed monolayers of varying amounts of such monomers at the air/water interface can be converted by photo-irradiation into the corresponding covalently connected monolayer sheets. Since one of the monomers carries three anthracene units and the other three 1,8-diaza-anthracene units, the growth reaction is proposed to take place through photochemically achieved [4+4]-cycloaddition between pairs of these units that are co-facially (face-to-face) arranged, to furnish the corresponding covalent dimers. While evidence for both homodimers is amply available, the existence of the heterodimer needs to be established with the help of a model reaction to support the conceptual aspect of this work, copolymerization in two dimensions. The sheet copolymers exhibit substantial robustness in that they can be spanned over 20 × 20 µm(2)-sized holes without rupturing under their own weight. X-ray photoelectron spectroscopy (XPS) studies reveal that the monomers are incorporated into the sheet copolymers according to feed. These results establish existence of the first covalent sheet copolymer, which is considered a step ahead towards novel 2D materials.

Photoactivated cyclization of aryl-containing enediynes coated gold nanoparticles: enhancement of the DNA cleavage ability of enediynes.

Two novel enediynes containing an aromatic ring and substituted by two thiol functions as end-groups were designed and studied as functionalizing agent of gold nanoparticles. Phototriggered cyclization of the capping agent under UV-visible irradiation was investigated. Interestingly, the length of the thiol-substituted chain was shown to influence significantly the cyclization rate. Depending on the length of the spacer, either polymerization or simple cyclization of the coating agent was evidenced. The present study underscores the possibility of finely controlling the fate of the coating agent (polymerization/cyclization). Nanocomposites were characterized by UV-visible absorption spectroscopy, dynamic light scattering (DLS) technique and transmission electron microscopy (TEM) measurements. Finally, the ability of the colloidal solutions to induce photoinitiated damages to PcDNA3 supercoiled DNA was evaluated. Interestingly, an increase as high as 50% of the DNA cleavage could be registered when adding enediynes-capped gold nanoparticles to solutions of enediynes. In particular, the enhancement of DNA scission was observed in both thermal and photochemical activation modes.

Preparation and properties of cyclic acetal based biodegradable gel by thiol-ene photopolymerization.

Synthetic, hydrolytically degradable biomaterials have been widely developed for biomedical use; however, most of them will form acidic products upon degradation of polymer backbone. In order to address this concern, we proposed to fabricate a biodegradable gel based on the crosslinking of a cyclic acetal monomer with reactable diallyl group and multifunctional thiols by thiol-ene photopolymerization. This gel produces diols and carbonyl end groups upon hydrolytic degradation and could be entirely devoid of acidic by-products. Real time infrared spectroscopy was employed to investigate the effect of different light intensities and concentrations of photoinitiator on the polymerization kinetics. With the increase of the concentration of photoinitiator and light intensity, both the rate of polymerization and final double bond conversion increased. Degradation of cyclic acetal based networks was investigated in PBS medium so as to simulate physiological conditions. The remaining mass of the materials after 25 days incubation was 84%. TGA analysis showed that the gels exhibited a typical weight loss (97.2%) at around 378 °C. In vitro cytotoxicity showed that the cyclic acetal based gels had non-toxicity to cell L-929 and had good biocompatibility.

Transient X-ray fragmentation: probing a prototypical photoinduced ring opening.

We report the first study of UV-induced photoisomerization probed via core ionization by an x-ray laser. We investigated x-ray ionization and fragmentation of the cyclohexadiene-hexatriene system at 850 eV during the ring opening. We find that the ion-fragmentation patterns evolve over a picosecond, reflecting a change in the state of excitation and the molecular geometry: the average kinetic energy per ion fragment and H(+)-ion count increase as the ring opens and the molecule elongates. We discuss new opportunities for molecular photophysics created by optical pump x-ray probe experiments.

Photodegradation of fleroxacin injection: different products with different concentration levels.

Photodegradation of fleroxacin is investigated in different injections and solutions. After UV irradiation, fleroxacin was degraded to afford two major products in large-volume injection (specification, 200 mg:100 ml), while degraded to afford another major product in small-volume injection (specification, 200 mg:2 ml). The photodegradation products were detected and isolated by reversed-phase HPLC. Based on the spectral data (FT-IR, MS(n), TOF-MS, (1)H/(13)C, DEPT, and 2D NMR), the structures of these products were: 8-fluoro-9-(4-methyl-piperazin-1-yl)-6-oxo-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid (impurity-I); 6-fluoro-1-(2-fluoro-ethyl)-7-(2-methylamino-ethylamino)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (impurity-II); and 6,8-difluoro-1-(2-fluoro-ethyl)-7-(2-methylamino-ethylamino)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (impurity-III), respectively. Different photodegradation pathways of fleroxacin were proposed, which led to the different stability characteristics of fleroxacin in the injections. The fluorine atom at C8 is more photolabile in dilute injection, so defluorination and cyclization reactions are prone to take place, whereas photo irradiation only cause ring-opening oxidation reaction of piperazine side chain in concentrated injection.

Crystal structures of thiobarbiturate with N-phenylalkyl group and its photocyclization product.

The photo-irradiation of thiobarbiturates (1) with an N-phenylalkyl group gives bicyclic fused pyrimidine derivatives (2) through a Norrish type II reaction. The crystal structures of dihydro-1,5,5-trimethyl-3-(3-phenylpropyl)-2-thioxo-4,6(1H,5H)-pyrimidinedione (1a) and the photocyclization product (2b) of dihydro-1,5,5-trimethyl-3-(3-phenylbutyl)-2-thioxo-4,6(1H,5H)-pyrimidinedione (1b) were elucidated by X-ray crystallographic analysis. The photocyclization product (2b) was determined to be 1,6,7,8-tetrahydro-1,3,3-trimethyl-9-phenyl-2H-pyrido[1,2-a]pyrimidine-2,4(3H)-dione.

The (5-4) and (6-4) adducts of 1-methylthymine and their Dewar valence isomers.

Previous studies of the photochemical reaction of 1-methylthymine (MeT) in frozen aqueous solution have indicated that four cyclobutane type dimers are formed. We have restudied this system and have found that, in addition to cyclobutane dimers, both a (5-4) adduct and a (6-4) adduct of MeT are formed in significant amounts. Upon standing in aqueous solution, the (5-4) adduct is susceptible to reaction to form an isomeric form of the parent adduct, possibly via ring-opening and closure reactions at C-6 of the saturated pyrimidine ring component of the adduct. Irradiation of each of these three adducts with UVB light produces a pair of Dewar-type adducts. The nine products were individually characterized by mass spectrometry, proton NMR spectroscopy and UV spectroscopy. A less comprehensive study showed that irradiation of thymidine in frozen aqueous solution produces a diastereomeric pair of (5-4) adducts, along with the previously known diastereomeric pair of (6-4) adducts.

Zinc triflate: a highly efficient reusable catalyst in the synthesis of functionalized quinolines via Friedlander annulation.

An environmentally friendly and highly efficient procedure for the preparation of quinolines and fused polycyclic quinolines has been developed by a simple Friedlander annulation reaction of 2-aminoaryl ketone with carbonyl compounds in presence of zinc triflate under microwave irradiation and solvent-free conditions. The reaction also proceeds effectively when In(OTf)(3) was used in lieu of Zn(OTf)(2) as the catalyst. The catalyst can be recovered after the reaction and reused efficiently in subsequent runs.

A photocontrolled molecular switch regulates paralysis in a living organism.

Using light to modulate biochemical agents in living organisms has a significant impact on photodynamic therapy and drug release. We demonstrate that a photoresponsive system can reversibly induce paralysis in nematodes as a model for living organisms when two different wavelengths of light are used to toggle the molecular switch between its two structural forms. This example illustrates how photoswitches offer great potential for advancing biomedical technologies.

Metal-free, retro-cycloaddition of fulleropyrrolidines in ionic liquids under microwave irradiation.

Quantitative cycloreversion of fulleropyrrolidines to [60]fullerene is achieved in ionic liquids within minutes under microwave irradiation without any further additives.

Palladium-catalyzed decarboxylative rearrangements of allyl 2,2,2-trifluoroethyl malonates: direct access to homoallylic esters.

Homoallylic esters are obtained in a single transformation from allyl 2,2,2-trifluoroethyl malonates by using a Pd(0) catalyst. Facile decarboxylation of allyl 2,2,2-trifluoroethyl malonates is attributed to a decrease in pK(a) compared to allyl methyl malonates. Subsequent reduction of the homoallylic 2,2,2-trifluoroethyl ester provides a (hydroxyethyl)cyclopentenyl derivative that represents a key intermediate in the synthesis of carbocyclic nucleosides. A select allyl 2,2,2-trifluoroethyl malonate undergoes a decarboxylative Claisen rearrangement to provide a regioisomeric homoallylic ester.

Amino substituted bisketenes: generation, structure, and reactivity.

Hitherto unknown diamino-substituted bisketenes with both free (14) and tethered (16) amino substituents have been generated by using laser flash photolysis for ring opening of the corresponding cyclobutenediones. The time-resolved kinetics of ring closure of the amino bisketenes back to the cyclobutenediones were measured by IR or UV spectroscopy, and give first-order rate constants which vary by a factor of 7.5x10(4), and the bis(Me2N) bisketene 14 is the most reactive in ring closure that has been reported. Rate constants for ring closure of these and previously observed bisketenes vary by a factor of 10(13). The dialkylamino bisketenes 16 (R=Me, n-Bu) with tethered substituents and restricted geometries are less reactive than the bis(Me2N) bisketene 14 by factors of 1700 and 540, respectively. Computational results obtained with DFT methods suggest angle strain in the tethered cyclobutenediones 15 inhibits facile cyclization of bisketenes 16.

Microwave assisted IMDAF# reaction: microwave irradiation applied with success to cycloaddition reaction of N-propargyl-N-p-tolyl-N-2-furfurylamines.

The new tertiary furfurylamine with triple bond as a dienophylic part i.e. N-(5-methyl-2-furfuryl)-N-prop-2-ynyl-p-toluidine (1) was prepared and the intramolecular Diels-Alder reaction of the amine (1) was performed under microwave irradiation conditions and by heating a benzene solution of the amine under nitrogen. Comparing the results of the usual thermal and the MAOS reaction, we confirmed our expectations that MAOS could promote the outcome of IMDA reaction of the suitably N-substituted tertiary 2-furfuryl-amines. In the present example, N-p-tolyl-5-methyl-5,7a-dihydro-5,7a-epoxyisoindoline was obtained in much better yield and of higher purity.