Abstract
The primary chemical reactions of singlet molecular oxygen with polyunsaturated carotenoids are the focus of this research report. Model compounds that exhibit electronic properties and substituent pattern similar to natural carotenes, xanthophylls or apocarotenoids, respectively, were investigated with regard to photooxygenation reactivity. For dienes and trienes as substrates, high tandem reactivity was observed and hydroperoxy-endoperoxides were isolated as the secondary products of singlet oxygen reaction. The electronic gem-effect on the regioselectivity of the ene reaction is conserved also in vinylogous positions and thus appears to originate from a radical-stabilizing effect. In an attempt to combine different peroxide groups derived from natural products as a tool for new pharmaceutically active products, a dyade synthesis of an artemisinine-safranol with subsequent singlet oxygen addition was realized.
Carotenoids as singlet oxygen quencher
In natural photosynthesis, electronic energy transfer from the excited triplet chlorophyll to molecular oxygen (thereby generating singlet oxygen, 1O2) is an unavoidable process due to the components that interact in the reaction center of the photosystem II [1]. The formation of reactive oxygen species (ROS) such as 1O2 and other molecules like superoxide and hydrogen peroxide, respectively, becomes especially critical under light stress (high light) [2]. Under these conditions, molecular protecting mechanisms operate that have either to be up regulated or to be always available [3]. A prominent tetraterpene that is present in the photosystem II is β-carotene (1), an essential component with a specific protection task [4]. Another well-known carotene is the tetraterpene lycopene (2), a deep red compound especially abundant in tomatoes [5]. These carotenes and the partially oxygenated xanthophylls (Scheme 1) are abundant in nature and many of these compounds are known for their ability to quench singlet oxygen predominantly in a physical quenching way [6]. This quenching process can approach the diffusion limit [7] and leads to excited state deactivation without chemical changes of the quencher molecules. Under cellular conditions, this protective (“antioxidative”) behaviour was recently challenged for β-carotene [8]. Physical and chemical quenching constants were determined for numerous carotenoids and apocarotenoids and range from 108 to 1010 M−1s−1 [9]. Among these natural compounds, crocin, a α,ω-dimethylated tetradecaheptaene 1,14-dicarboxylic acid (3), is described to chemically react with singlet oxygen with a rate constant of 0.56 × 108 M−1s−1 in water [10]. The corresponding bixines are γ-methylated octadecanonaenes (4) with similar singlet oxygen reactivity. Obviously, these compounds have multiple sites for singlet oxygen reactions and diverse primary and secondary processes are expectable. Under non-cellular solution-phase conditions, lycopene is even more potent than β-carotene in singlet oxygen quenching processes [11, 12]. Surprisingly, no detailed investigations on the primary reaction products of these natural antioxidants with singlet oxygen were performed. An exception is β-carotene where solution phase investigations have already been reported in the 1970s by Foote and Denny [13] and a mono-endoperoxide was reported as the first singlet oxygen chemical quenching product from 4 + 2-cycloaddition with the terminal 1,3-diene moiety [14]. Three other mono- and bis-endoperoxides were characterized as products of its sensitized photooxygenation [15].
What we do not know yet
The chemical and physical quenching properties of numerous carotenoids, i.e. carotenes, and xanthophylls, as well as the oxidative degradation products apocarotenoids have been determined by detailed physical measurements, e.g. the singlet oxygen phosphorescence methods or by HPLC-MS investigations of complex oxygenated product mixtures. In numerous cases, degradation of carotenoids result in the formation of low-molecular weight oxidation fragments such as C5, C10, C15 or C20 aldehydes or ketones. They derive from the enzymatic degradation of primary and secondary oxygenation products, i.e. hydroperoxides and endoperoxides, from ene reaction and 4 + 2-cycloaddition with singlet oxygen, and 1,2-dioxetanes from 2 + 2-cycloadditions with singlet oxygen. Due to the symmetric structures of most carotenoids and xanthophylls, these peroxides are formed at both sides of the polyenes with identical probabilities (e.g. ene reactions at the terminal double bonds of lycopene) and, subsequently, secondary singlet oxygen processes can happen. How fast these secondary processes are is not known yet. Additionally, tandem or cascade reactions can be triggered due to the structural changes that result as a consequence of the first singlet oxygen reaction. These polyperoxides are also not known yet. The biological significance of the primary and secondary oxygenation products is also not known due to the lack of structural information as well as material.
Singlet oxygen reactivity modes
From a classification that goes back to a suggestion by the late Chris Foote, photooxygenation reactions were defined as Type I, II, [16] and subsequently also Type III for electron-transfer oxygenation. The Type I process involves reactions of carbon radicals or radical ions with triplet oxygen or the superoxide anion. Type II photooxygenation involves singlet oxygen (1O2) as the reactive species that is generated by energy transfer photosensitization [17].
One of the most favorable singlet oxygen reactions is the Schenck ene reaction with monoalkenes that possess allylic hydrogens (Scheme 2) [18]. Similar to other thermal ene reactions with electrophilic enophiles (such as nitroso compounds, Michael systems, carbonyl compounds), this process prefers electron-rich alkenes: tetraalkylated alkenes are favored over trialkylated substrates by a factor of 10 [19]. The different regioselectivity pattern, however, did not support a typical concerted process [20, 21]. The long-known “cis-effect” in a versus b [21] is abundant in polyalkylated substrates, e.g. in the allylic substituted alkenes c or the trialkylated and allylic hydroxylated compounds d–f. Beside this kinetic effect, the “gem effect” is most unusual because electron-poor substrates with α-methyl groups g (α,β-dialkylated acrylates and derivatives) add 1O2 with high regioselectivity to give the conjugated allylic hydroperoxides [22]. Tiglic acid derivatives result in regioisomeric hydroperoxide ratios of 95:5 up to 98:2. This effect was also observed for α,β-unsaturated nitriles [23] sulfoxides [24], and sulfonates [25]. Also the corresponding dimethylstyrene showed gem-selectivity [26]. A third and less intensively investigated effect is the “non-bonding large-group effect” [27]. The mechanistic course of the singlet oxygen ene reaction is currently best described by a two-step no-intermediate mechanism involving a bifurcating transition state with perepoxide structure as proposed by Houk et al. [28]. Small changes in the substrate structure can also open a low-energy pathway via a real perepoxide intermediate [29]. The valley ridge model [30] appears to be a powerful explanation of the cis-effect (vide infra) as well as deviations that result from geometrical constraints of the allylic hydrogen atoms [31]. The special behavior in the reaction of 1O2 with electron-deficient Michael systems (e.g. preferred α-alkyl CH transfer) was already recognized by Foote et al. as an indication for a two-step process involving asymmetric perepoxide intermediates [32]. Following a theoretical approach, Maranzana et al. have postulated that α,β-unsaturated carbonyl compounds are prone to form biradical intermediates in Schenck ene-type reactions [33]. Whether this is relevant also to the singlet oxygen reactivity with highly conjugated systems that exist in carotenes and xanthophylls, has not yet been proven experimentally.
Alkylated acyclic 1,3-dienes show competing reactivity between ene and 4 + 2-cycloaddition [34]. Semiempirical calculations suggested that a stable perepoxide intermediate for the butadiene/singlet oxygen reaction is feasible [35]. An orbital correlation approach analyzes the [4 + 2] cycloaddition reaction of singlet oxygen with 1,3-dienes as a stepwise process [36]. Sevin and McKee have computated the reaction of singlet oxygen with 1,3-cyclohexadiene at the B3LYP and CASPT2 levels [37]. They found a stepwise pathway in which a diradical is formed in the first step with an activation barrier of 6.5 kcal/mol. The second transition structure has a lower energy than the diradical intermediate and for this reason, the reaction can also be considered as a nonsynchronous concerted reaction. Bobrowski et al. studied the 1,4-cycloaddition of singlet oxygen with both s-cis-1,3-butadiene and benzene by CAS SCF ab initio methods [38]. They propose a diradical intermediate on the lowest energy pathway [MCQDPT2/6-31G(d)] of the reaction of singlet oxygen with s-cis-butadiene to the endoperoxide. The stereoselectivity of singlet oxygen addition to 1,3-dienes was originally investigated by Rigaudy et al. [39]. For diastereomeric 2,4-hexadienes, singlet oxygen induced E/Z-isomerization was determined at the stage of an intermediate biradical [40]. Thus, multistep processes are the most convincing description for singlet oxygen ene reactions and 4 + 2-cycloadditions involving non-trappable intermediates or no intermediates at all.
Model compounds for apocarotenoids
In an initial approach to this problem, we identified three critical substrate motifs in apocarotenoids (Scheme 3): (a) the tiglate-type structure with the potential ene-reactive α-methyl group, (b) α- vs. γ-methylated diene ester, and (c) α, γ-methylated triene ester motifs. In our preliminary studies, we investigated the (chemical) singlet oxyen reactivity with these structural motifs, i.e. the influence of ß-vinylation of the methacrylate system in type (a) and the introduction of methyl groups at α, γ, and δ-positions of enone esters as existent in type (b) and (c). All experiments were initially performed in 2 × 10−4 M solutions of the singlet oxygen sensitizer meso-tetraphenylporphyrin (TPP) in deuterochloroform solutions at room temperature with an initial 200 mM concentration of the substrates. These solutions were irradiated with white LED lamps in NMR tubes (for analytic runs, 1–2 mL of solvent) or Schlenk tubes (for preparative runs, 20–30 mL of solvent). Other solvents were subsequently applied in with rose bengale (RB) as the sensitizer for polar aprotic (acetone, acetonitrile) and protic (ethanol) solvents.
Results with terminal polyene esters
In the gem-selective substrates mentioned before, the kinetic cis-effect exists that does not propagate to product formation, a typical phenomenon of two-step reaction mechanism. In order to evaluate this kinetic contribution, we compared the reactivity difference between the E- and Z-isomers of the 2-butene carboxylic acid methyl ester 5a. Both stereoisomers result in the (gem-type) allylic hydroperoxide 6a with diastereoselectivities >98 %, i.e. there is no cis effect on the product-forming step. The kinetic cis effect was determined from the pseudo first order substrate consumption curves [41]. The curve progression switch to second order behavior after 70 % conversion and a kinetic cis effect of 5.2 was determined for E-5a/Z-5a, slightly higher than the kinetic effect for the cis/trans-2-butene couple [42]. A decrease of the kinetic cis effect must occur with a decreasing number of allylic hydrogens at the β-alkyl group. The β-ethyl substrate 5b reacted slightly faster with 1O2 possibly resulting from 1,3-allylic strain that positions the allylic hydrogens in the optimal perpendicular orientation on both sides of the π-system. This effect breaks down for one side of the π-system for the β-isopropyl substrate 5c and completely for the tert-butyl substrate 5d resulting in a relative kinetic situation of 1:1.2:0.6:0.05 for 5a:5b:5c:5d (Scheme 4). The incorporation of the β-vinyl group in 5e resulted in a substantial electronic modification of the tiglate system. This substrate shows solvent-dependent mode selectivity, i.e. 4 + 2 versus ene reaction with 1O2. The ene reaction that is suspected to proceed via a more polar transition state compared to the asynchronous [4 + 2] process, became the dominant process in polar protic solvents. The kinetic comparison with substrate 5b with maximum kinetic cis-effect shows a rate decrease by a factor of 40 for the ene reaction with 5e. Overall, the mode selectivity (i.e. ene versus 4 + 2 reaction mode) is low for this substrate with no ene regio-differentiation.
A comparable solvent effect on the mode selectivity was determined for the α,δ-dimethylated substrate 5f (Scheme 5). The additional δ-methyl group was completely inert under the reaction conditions in all solvents even after prolonged irradiation time and the ene product 6f from α-hydrogen transfer dominates the 4 + 2-cycloadduct 8 in ethanol. The additional methyl group in 5f accelerated the singlet oxygen reaction by a factor of five in comparison with 5e. The picture changed substantially for the α,γ-dimethylated substrate 5g. The solvent effect on the mode selectivity vanished nearly completely and under all solvent conditions, the endoperoxide 9 was obtained as the major product with complete conversion in non-polar solvents after less than 24 h. Comparing the reactivity of the two methyl groups at α- and γ-position, the α-hydrogen transfer product 6g was observed and isolated as the respective allylic alcohol whereas less than 2 % of the γ-hydrogen transfer product was observed by 1H NMR. As the next diene substrate, the γ,δ-dimethylated 5h was investigated as the pure E,E-diastereoisomer as well as a 9:1 mixture of E,Z- and E,E-diastereoisomers. In both cases, rapid singlet oxygen addition delivered the allylic hydroperoxide 6h as the sole product after >90 % conversion of the starting material. Even faster were the singlet oxygen reactions with the α,γ,δ-trimethylated substrates 5i, also applied as the pure E,E-diastereoisomer as well as a 4:1 mixture of E,Z- and E,E-isomers which delivered the allylic hydroperoxide 6i. In both cases, only trace amounts of the corresponding 4 + 2 cycloadducts (10, 11) were observed in the NMR spectra. When further treating the substrate solutions with singlet oxygen, the tandem products 12 and 13, respectively, were formed (vide infra). The most reactive substrate in this series of 1,3-diene carboxylates is the E,E-isomer of 5i. Obviously, this substrate profits from the kinetic cis effect as well as from the highly nucleophilic diene structure. Remarkably, substrate 5i has the largest number of reaction possibilities, three different methyl groups for ene reactions as well as the 1,3-diene moiety for 4 + 2-cycloaddition. Conformational reasons cannot be responsible for the prevalence of the ene process because no substantial difference in s-cis/s-trans conformational ratio can be expected for 5g in comparison with E,E-5i. Thus, this scenario of mode and ene-regioselectivity is a perfect example for a kinetic Curtin–Hammett situation.
Under homogeneous photooxygenation reaction conditions, the initially formed product 6h did add another equivalent of 1O2 after prolonged reaction time and the hydroperoxy-endoperoxide 12 was isolated in 86 % yield as a mixture of diastereoisomers (Scheme 6) [43]. In order to study the diastereoselectivity of the second 1O2 addition, we applied the hydroxy-directing effect for 4 + 2-cycloadditions that was reported for chiral dienols as substrates [44]. Therefore, the hydroperoxide 6h was reduced to the allylic alcohol 14 with dimethylsulfide and converted into the endoperoxide 16. Surprisingly, a further decrease in diastereoselectivity was observed with a slight increase in ene reactivity.
Subsequently, the α-methylated 1,3-diene ester E,E-5i was investigated in order to evaluate the degree of vinylogous gem (γ-CH transfer) versus normal (α-CH transfer) gem-selectivity. Due to the additional methyl group (in comparison with 5h), the primary 1O2 reaction is accelerated and the hydroperoxide 6i was observed as sole product after 1.5 h. The subsequent [4 + 2]-cycloaddition with 1O2 proceeded rapidly with the allylic hydroperoxide 6i as well as with the corresponding allylic alcohol 15. These products were formed in identical mode and regioselectivity from E,Z-5i, available from methy tiglate. The highly selective first step of the domino reaction with the di- and trimethylated substrates 5h and 5i, respectively, reveals a strong vinylogous gem-effect in singlet oxygen ene reactions. By this effect, the 1,3-diene structure is retained and subsequent Diels–Alder reactivity with 1O2 is obtained. This type of a domino (or, more correctly, a diene-transmissive sequence) photooxygenation process [45–47] requires an acceptor group at the terminal carbon (Acc = COOR, COOH, CHO) and can be easily performed as a one-pot process.
An extended application of the terminal polyene ester principle is shown in Scheme 7 for the 1,3,5-triene ester 18. The first singlet oxygen addition was completed in less than 1 h irradiation time (substrate:sensitizer ratio = 1000:1) in deuterated chloroform (2×10−4 M in tetraphenyl-porphyrin, TPP) and a 93:7 ratio of ene product 19 and a 4 + 2-cycloaddition product (not shown) was isolated [48]. With increasing reaction time, the tandem product 20 was formed with complete conversion after 10 h. Due to this rate difference in primary vs. secondary singlet oxygen reaction, the hydroperoxide 19 could be isolated and subsequently reduced to the triene alcohol 21. Photooxygenation of this molecule leads to the hydroxy-endoperoxide 22. As an alternative oxyfunctionalization process from 19, titanium (IV)-catalyzed oxygen transfer reaction results in the epoxide 23 in good yields.
Combinations of natural product motifs for singlet oxygenation
The interest in this field of photochemistry arises from the search in effective antimalarial peroxides, an intensively investigated area in medicinal chemistry [49]. The natural sesquiterpene peroxide artemisinin (qinghaosu), used since centuries in Chinese folk medicine as a plant extract, has initiated and stimulated this field of research [50]. The enormous potency of the natural product that involves also anti-cancer drug activity just recently emerged [51, 52]. At the same time, however, reports appeared that describe the appearance of malaria-producing plasmodium species resistant against artemisinin and artemisinin-derivatives [53, 54]. Three approaches currently try to deal with this fatal trend: a) artemisinin combination therapy (ACT, with other non-peroxidic antimalarial drugs) [55], b) new peroxidic substances following the structural prototype [56, 57], c) dyade concepts [58] involving structure combinations of two artemisinin monomers [59], artemisinin and quinolines [60], or artemisinin derivatives with synthetic 1,2,4-trioxane structures [61, 62]. In this context, also the natural endoperoxide ascaridole was described as one potential dyade partner molecule [63]. In order to explore new structural motifs, we envisaged other natural occuring terpenoids with pre-endoperoxide structures. One attractive example is the trimethylated cyclohexadiene safranal.
Safranal constitutes the major spice component of crocus flowers together with crocin, crocetin and picocrocetin (vide supra), and is crucial for the aroma of saffron [64]. The photooxygenation of the safranal was however slow and delivered the corresponding endoperoxide as an unstable compound. Therefore, the dyade concept was reversed and the nucleophilic part allocated to the endoperoxide component, i.e. conversion of the aldehyde safranal to the corresponding alcohol 25 and subsequent photooxygenation [65]. The endoperoxide 26 was completely stable at room temperature. In order to accomplish a dyade synthesis from endoperoxide 26 and an artemisinin skeleton, the Steglich esterification of 26 with artesunate 24 was investigated; a well-known process with numerous alcohols. In contrast to the literature reports coupling was not successful and led to Broensted-acid catalyzed decomposition of the alcohol component. Consequently, safranol 25 was used as the alcohol component and esterificated with artesunate using DCC/DMAP to give the ester 27 in 19 % isolated yield. Photooxygenation under standard conditions led to the desired trioxane-endoperoxide couple 28 in 21 % yield (Scheme 8).
Conclusions
Nature offers a variety of polyunsaturated substances that are highly reactive with singlet oxygen and quench this excited state by a combination of physical and chemical quenching. Singlet oxygen is a by-product of the photosynthetic machinery and thus, the primary and secondary oxygenation products are interesting compounds that might have diverse biological function. We have shown for a series of model substrates that singlet oxygen ene and 4 + 2-cycloadditions follow regio-selectivity rules and tandem products can be produced as well as peroxide dyades.
Article note
A collection of invited papers based on presentations at the XXVth IUPAC Symposium on Photochemistry, Bordeaux, France, July 13–18, 2014.
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