Ene Reaction Of Singlet Oxygen Research Articles

Regioselectivity in the ene-reaction of singlet oxygen with cyclic alkenes: photooxygenation of methyl-substituted 1,4-cyclohexadiene derivatives

The photooxygenation of the 1-methyl-, 2,3-dimethyl-, and 1,4-dimethylcyclohexa-1,4-dienes, which are readily available through Birch reduction, yielded the corresponding ene-products. The formed endocyclic dienes were trapped by the addition of singlet oxygen to give the corresponding bicyclic endoperoxy hydroperoxides. In the case of 1-methylcyclohexa-1,4-diene and 1,4-dimethylcyclohexa-1,4,-diene, the cis-effect determined the product distribution. Photooxygenation of 2,3-dimethylcyclohexa-1,4-dienes gave mainly exocyclic olefin, which was attributed to the lowered rotational barrier of the methyl group and increased reactivity of the methyl groups.

Intrazeolite photooxygenation of chiral alkenes. Control of facial selectivity by confinement and cation–π interactions

Depending on the nature of the substituents on the stereogenic carbon atom, the ene reaction of singlet oxygen with several chiral alkenes by confinement within thionin-supported zeolite NaY, may exhibit significant changes on facial selectivity by comparison to their photooxygenation reaction in solution. It is proposed that, apart from the conformational consequences as a result of the alkene confinement within the zeolite cavities, a synergism between Na +–π interactions and singlet oxygen–Na + interactions plays a significant role in the transition states of ene hydroperoxidation. Within NaY, the diastereoselectivity may significantly depend on the site selectivity, as probed through specific deuterium labelling of trisubstituted alkenes bearing a gem-dimethyl group. In certain cases, a remote stereogenic centre relative to the reacting double bond may induce enhanced diastereoselection and regioselectivity.

Singlet oxygen addition to chiral allylic alcohols and subsequent peroxyacetalization with β-naphthaldehyde: synthesis of diastereomerically pure 3-β-naphthyl-substituted 1,2,4-trioxanes

The synthesis of a series of eight β-naphthyl-substituted 1,2,4-trioxanes 3a– h by a sequence of singlet oxygen ene reaction of allylic alcohols 1a– h and Lewis acid catalyzed peroxyacetalization of the allylic hydroperoxides 2a– h with β-naphthaldehyde is reported. The ene reactions were performed by solid-state photooxygenation in dye-crosslinked polystyrene beads and resulted in mixtures of diastereoisomeric hydroperoxides 2. Boron trifluoride catalyzed peroxyacetalization resulted in the formation of 3, as well as the 1,2,4-trioxanes 4 and 5, which were formed via acid catalyzed β-hydroperoxy alcohol cleavage.

Stereoselectivity in Ene Reactions with 1O2: Matrix Effects in Polymer Supports, Photo‐oxygenation of Organic Salts and Asymmetric Synthesis

The ene reaction of chiral allylic alcohols is applied as a tool for the investigation of intrapolymer effects by means of the stereoselectivity of the singlet-oxygen addition. The diastereo selectivity strongly depends on the structure of the polymer, the substrate loading degree and also on the degree of conversion demonstrating additional supramolecular effects evolving during the reaction. The efficiency and the stability of polymer-bound sensitizers were evaluated by the ene reaction of singlet oxygen with citronellol. The ene reaction with chiral ammonium salts of tiglic acid was conducted under solution phase conditions or in polystyrene beads under chiral contact ion-pair conditions. The products thus obtained precipitate during the photoreaction as ammonium salts. Moderate asymmetric induction was observed for this procedure for the first time.

A Comparison of Intrazeolite and Solution Singlet Oxygen Ene Reactions of Allylic Alcohols

The singlet oxygen ene reactions of four allylic alcohols and for comparison an allylic ether have been examined both in solution and in zeolite Y. Brønsted acid sites in the zeolite were shown to induce decomposition of several of the allylic alcohols. Treatment of the zeolites with pyridine removed these acid sites and allowed intrazeolite reactions of the allylic alcohols without interference from decomposition. Control reactions with an allylic alcohol that is inert to decomposition provided evidence that the presence of pyridine in the zeolite labyrinth does not influence the product composition.

Type II photooxygenation in polymer matrices for the synthesis of new antimalarial peroxides

Type II photooxygenation involves the photochemical activation of dioxygen into its first excited singlet state and the application of this reactive species in oxy-functionalization of organic molecules. A broad variety of reactions and substrates can be applied in type II processes. The efficiency is determined by the lifetime of the 1Δ g-dioxygen and the physical as well as the chemical quenching rates by the substrate. The singlet oxygen ene reaction with allylic alcohols was developed as a route to mono- and spirobicyclic 1,2,4-trioxanes, molecules which showed moderate to high antimalarial properties similar to the naturally occurring sesquiterpene-peroxide artemisinin. As sensitizing materials tetraarylporphyrins embedded in polystyrene (PS) beads or in polymer films were used. Alternatively, the sensitizers were covalently linked to polystyrene during emulsion polymerization. The diastereoselectivity of the ene reaction with chiral allylic alcohols served as a probe for the microenvironment in the polymer matrices. Applications of this technique for the synthesis of a multitude of peroxides are described.

Theoretical Study on the Reactivity and Regioselectivity of the Ene Reaction of 1Δg O2 with α,β‐Unsaturated Carbonyl Compounds

AbstractThe ene reaction of singlet oxygen with α,β‐unsaturated carbonyl compounds gives unsaturated hydroperoxides and displays interesting features: Different reactivities of the s‐cis and s‐trans reactants and a marked regioselectivity, influenced to some extent by solvent polarity. All of these traits are accounted for by a polar diradical mechanism. A perepoxide intermediate is not a critical point on the reaction’s potential energy surface. Also, a trioxene intermediate is located too high in energy to be significantly populated. An alternative pathway leading to dioxetane is not as effective as the ene pathway giving the hydroperoxide. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Photooxygenation in polymer matrices: En route to highly active antimalarial peroxides

Abstract Photooxygenation involving the first excited singlet state of molecular oxygen is a versatile method for the generation of a multitude of oxy-functionalized target molecules often with high regio- and stereoselectivities. The efficiency of singlet-oxygen reactions is largely dependent on the nonradiative deactivation paths, mainly induced by the solvent and the substrate intrinsically. The intrinsic (physical) quenching properties as well as the selectivity-determining factors of the (chemical) quenching can be modified by adjusting the microenvironment of the reactive substrate. Tetraarylporphyrins or protoporphyrin IX were embedded in polystyrene (PS) beads and in polymer films or covalently linked into PS during emulsion polymerization. These polymer matrices are suitable for a broad variety of (solvent-free) photooxygenation reactions. One specific example discussed in detail is the ene reaction of singlet oxygen with chiral allylic alcohols yielding unsaturated β-hydroperoxy alcohols in (threo) diastereoselectivities, which depended on the polarity and hydrogen-bonding capacity of the polymer matrix. These products were applied for the synthesis of mono- and spirobicyclic 1,2,4-trioxanes, molecules that showed moderate to high antimalarial properties. Subsequent structure optimization resulted in in vitro activities that surpassed that of the naturally occurring sesquiterpene-peroxide artemisinin.

Novel regiochemistry in the aqueous singlet oxygen ene reactions of carboxylic acid salts: a comparison of substrate structure

The singlet oxygen ( 1Δ g) photooxidations of angelic acid salt ( 1 ), tiglic acid salt ( 2 ), 2,3-dimethyl-2-butenoic acid salt ( 3 ), 3-ethoxycarbonyl-5,6-dihydro-2-methyl-4 H-pyrane acid salt ( 4 ), cis-3-hexenoic acid salt ( 5 ), and trans-3-hexenoic acid salt ( 6 ) were conducted in deuterated water. The major and minor ene allylic hydroperoxide products were quantified and indicate that the allylic hydrogen geminal to the carboxylate group is preferentially abstracted in 1– 4 , whereas the allylic hydrogen α to the carboxylate is slightly favored for 5 and 6 . We have attributed the observed regiochemistry in 1– 4 to stabilizing hydrogen bonding interactions between the solvent and the perepoxide, which leads to the major ene product.

Simple and Diastereoselective Synthesis of an A-Ring Precursor of Dihydroxyvitamin D3 (Calcitriol) by Photooxygenation

A convenient synthesis of a racemic A-ring precursor of dihydroxyvitamin D 3 (calcitriol) is described. The key step involves the singlet oxygen ene reaction of the Lythgoe lactone, which proceeds with excellent regio- and good diastereoselectivities. Strong polar interactions are operative during the attack of 1 O 2 to the double bond, which is important for the mechanism of such reactions.

Antimalarial xanthones from Calophyllum caledonicum and Garcinia vieillardii

The antimalarial activity of 22 xanthones against chloroquino-resistant strains of Plasmodium falciparum was evaluated. Natural caloxanthone C (1), demethylcalabaxanthone (2), calothwaitesixanthone (3), calozeyloxanthone (4), dombakinaxanthone (5), macluraxanthone (6), and 6-deoxy-γ-mangostin (7) were isolated from Calophyllum caledonicum. 1,6-dihydroxyxanthone (8), pancixanthone A (9), isocudraniaxanthone B (10), isocudraniaxanthone A (11), 2-deprenylrheediaxanthone B (12) and 1,4,5-trihydroxyxanthone (13) were isolated from Garcinia vieillardii. Moreover, synthetic compounds (14–22) are analogues or intermediates of xanthones purified from Calophyllum caledonicum (Oger J.M., Morel C., Hélesbeux J.J., Litaudon M., Séraphin D., Dartiguelongue C., Larcher G., Richomme P., Duval O. 2003. First 2-Hydroxy-3-Methylbut-3-Enyl substituted xanthones isolated from Plants: structure elucidation, synthesis and antifungal activity. Natural Product Research 17(3), 195–199; Hélesbeux J.J., Duval O., Dartiguelongue C., Séraphin D., Oger J.M., Richomme P., 2004. Synthesis of 2-hydroxy-3-methylbut-3-enyl substituted coumarins and xanthones as natural products. Application of the Schenck ene reaction of singlet oxygen with ortho-prenylphenol precursors. Tetrahedron 60(10), 2293–2300). The relationship between antimalarial activity and molecular structure of xanthones has also been explored. The most potent xanthones (2), (3) and ( 7) (IC50 = c.a. 1.0 μg/mL) are 1,3,7 trioxygenated and prenylated on the positions 2 and 8.

Enecarbamates as Selective Substrates in Oxidations: Chiral‐Auxiliary‐Controlled Mode Selectivity and Diastereoselectivity in the [2 + 2] Cycloaddition and Ene Reaction of Singlet Oxygen and in the Epoxidation by DMD and mCPBA.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Enecarbamates as selective substrates in oxidations: chiral-auxiliary-controlled mode selectivity and diastereoselectivity in the [2+2] cycloaddition and ene reaction of singlet oxygen and in the epoxidation by DMD and mCPBA.

The stereochemical course of the oxidation of chiral oxazolidinone-substituted enecarbamates has been studied for singlet oxygen ((1)O(2)), dimethyldioxirane (DMD), and m-chloroperbenzoic acid (mCPBA) by examining of the special structural and stereoelectronic features of the enecarbamates. Valuable mechanistic insight into these selective oxidations is gained. Whereas the R(1) substituent on the chiral auxiliary is responsible for the steric shielding of the double bond and determines the sense of the pi-facial diastereoselectivity, structural characteristic such as the Z/E configuration and the nature of the R(2) group on the double bond are responsible for the extent of the diastereoselectivity. Stereoelectronic steering by the vinylic nitrogen functionality controls the mode selectivity (ene reaction vs [2+2] cycloaddition) in the case of (1)O(2).

Synthesis of 2-hydroxy-3-methylbut-3-enyl substituted coumarins and xanthones as natural products. Application of the Schenck ene reaction of singlet oxygen with ortho-prenylphenol precursors

Application of our original photooxidation–reduction methodology to prenylated dihydroxycoumarin and trihydroxyxanthone compounds led to the corresponding ortho-(2-hydroxy-3-methylbut-3-enyl)phenol derivatives with yields ranging from 8 to 65%. In most of the reported experiments, the oxidation products distribution, after the photooxygenation step, was controlled by the competition between the large group effect and the stabilising phenolic assistance effect. We also showed that ortho-(3-hydroxy-3-methylbut-1-enyl)phenol derivatives could be considered as biogenetic precursors of 2,2-dimethylbenzopyranic structures.

Photooxygenation in Polystyrene Beads with Covalently and Non‐Covalently Bound Tetraarylporphyrin Sensitizers

AbstractTwo reaction protocols are described which involve the use of polymer supports as reaction media for photooxygenation processes: 1) The use of polystyrene beads (PS) loaded with tetraphenyl‐ (TPP) or tetratolylporphyrin (TTP), swollen with the substrate in an appropriate organic solvent and subsequent irradiation under air. Products were isolated simply by dissolution in alcoholic solvents and filtration. 2) Covalently linked tetrastyrylporphyrin in polystyrene‐divinylbenzene beads were synthesized by emulsifier‐free emulsion polymerization and directly used for the photooxygenation protocol described above. The latter alternative allows also the use of less polar solvents for the extraction of the oxygenation products from the polymer beads. From the sensitizer loading degree, an optimal substrate/sensitizer molar ratio of 1,000–2,000 was determined and recyclization is possible for at least five times resulting in a minimum turnover number (with respect to the sensitizer TTP) of 5×104 (after five cycles). Both approaches were applied to the ene reaction of singlet oxygen with citronellol (1), the regioisomeric pinenes 3 and 5, and the allylic alcohols 9a–c, respectively, as well as to the [4+2]‐cycloadditions of singlet oxygen to sorbinol (7) and the chiral diene 11.

12 Reaction mechanisms : Part (iii) Pericyclic reactions

Reports describing clever experimental studies and advanced computational studies continue to reveal the mechanistic complexity of seemingly simple pericyclic reactions. Some important examples are highlighted here. Experimental and computational evidence for the first two-step, no-intermediate reaction mechanism for the ene reaction of singlet oxygen with a simple alkene is presented by Singleton, Foote, Houk and co-workers. A new type of kinetic isotope effect due to dynamics is described by Singleton et al., discovered in their studies of the ene reaction involving singlet oxygen. Baldwin and Burrell report a study on the complicated thermal behavior of optically active trans and cis-1-(E)-propenyl-2-methylcyclobutanes. The following papers are relevant to several categories of pericyclic reactions. Otto and Engberts reviewed the importance of hydrophobic interactions on chemical reactivity, and include a discussion of Diels–Alder reactions, 1,3-dipolar cycloadditions, and Claisen rearrangements. Also, Houk and co-workers published a benchmarking study comparing experimental and computational data for eleven hydrocarbon pericyclic reactions. The authors' goals are: to establish reliable experimental data for comparative purposes; to determine what level of theory is necessary to calculate activation enthalpies with high accuracy; and to determine which density functional methods give reasonable results for pericyclic reactions. The most reliable activation enthalpies and heats of reaction are obtained using CASPT2 and CBS-QB3 methods. Some density functional methods also give very good activation enthalpies. All computational methods studied gave reasonable transition state geometries, with the exceptions of those for Cope rearrangement and cyclopentadiene dimerization.

Regioselectivity in the Ene Reaction of Singlet Oxygen with ortho‐Prenylphenol Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Remarkable change of the diastereoselection in the dye-sensitized ene hydroperoxidation of chiral alkenes by zeolite confinement.

[reaction: see text] The ene reaction of singlet oxygen with chiral trisubstituted alkenes bearing an alkyl and a phenyl group at the stereogenic center is erythro diastereoselective in solution and threo diastereoselective if carried out within zeolite Na-Y. The change of the diastereoselection trend by zeolite confinement is attributed to a synergism of steric effects and cation-pi interactions.

Photooxygenation of allylic alcohols: kinetic comparison of unfunctionalized alkenes with prenol-type allylic alcohols, ethers and acetates.

The kinetics of the chemical and physical quenching of the first excited singlet state of oxygen [1O2 (1delta(g))] by unfunctionalized alkenes 1-4, allylic alcohols 5-7 and 9, allylic acetates 8 and 11, and the allylic ether 10 display small solvent-polarity effects on the reactivity. The regioselectivity of the singlet oxygen ene reaction is solvent independent for the unfunctionalized alkenes as well as the prenol-type substrates, the latter showing substantial solvent effects on the diastereoselectivity. Pronounced physical quenching is detected only for the allylic alcohols 5 and 6. These results are interpreted in terms of the interactions between singlet oxygen and the allylic hydroxy groups, conformationally promoted by allylic strain which lead either to chemical activation or to physical quenching. The results for substrate 9 in deuterated v.s non-deuterated methanol are in accord with hydrogen bonding between the allylic alcohol and 1O2, which directs the diastereoselectivity of the ene reaction with chiral allylic alcohols.

Regioselectivity in the ene reaction of singlet oxygen with ortho-prenylphenol derivatives

The ene reaction of singlet oxygen with prenylated dihydroxyacetophenones led to the 2-hydroperoxy-3-methylbut-3-enyl derivatives as the major product. This original regioselectivity outlined a new effect, in competition with the previously established large group non-bonding effect. The oxidation products distribution could be explained by a stabilising interaction between the phenolic hydrogen, ortho to the prenyl side chain, and the perepoxide intermediate.