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Molecules 2017, 22(1), 119; doi:10.3390/molecules22010119

Article
Synthetic Approaches to Mono- and Bicyclic Perortho-Esters with a Central 1,2,4-Trioxane Ring as the Privileged Lead Structure in Antimalarial and Antitumor-Active Peroxides and Clarification of the Peroxide Relevance
Axel G. Griesbeck *, Maria Bräutigam, Margarethe Kleczka and Angela Raabe
Department of Chemistry, University of Cologne, Greinstr. 4, 50939 Köln, Germany
*
Correspondence: Tel.: +49-221-4703083
Academic Editor: Svetlana B. Tsogoeva
Received: 8 December 2016 / Accepted: 6 January 2017 / Published: 11 January 2017

Abstract

:
The synthesis of 4-styryl-substituted 2,3,8-trioxabicyclo[3.3.1]nonanes, peroxides with the core structure of the bioactive 1,2,4-trioxane ring, was conducted by a multistep route starting from the aryl methyl ketones 1a1c. Condensation and reduction/oxidation delivered enals 4a4c that were coupled with ethyl acetate and reduced to the 1,3-diol substrates 6a6c. Highly diastereoselective photooxygenation delivered the hydroperoxides 7a7c and subsequent PPTS (pyridinium-p-toluenesulfonic acid)-catalyzed peroxyacetalization with alkyl triorthoacetates gave the cyclic peroxides 8a8e. These compounds in general show only moderate antimalarial activities. In order to extend the repertoire of cyclic peroxide structure, we aimed for the synthesis of spiro-perorthocarbonates from orthoester condensation of β-hydroxy hydroperoxide 9 but could only realize the monocyclic perorthocarbonate 10. That the central peroxide moiety is the key structural motif in anticancer active GST (glutathione S-transferase)-inhibitors was elucidated by the synthesis of a 1,3-dioxane 15—with a similar substitution pattern as the pharmacologically active peroxide 11—via a singlet oxygen ene route from the homoallylic alcohol 12.
Keywords:
artemisinin; peroxides; singlet oxygen; hydroperoxides; 1,2,4-trioxane; orthoester

1. Introduction

The 2015 Nobel Prize in physiology and medicine awarded to the Chinese scientist Youyou Tu, for her discoveries concerning a novel therapy against malaria [1,2], honored a lifelong work in structure elucidation and investigations on mechanism of action of potent antimalarial drugs from folk medicine. The central compound in this research is the unusual peroxide artemisinin (in Chinese translation: qinghaosu), a structurally complex tetracyclic sesquiterpene lactone with an endoperoxide substructure that can be isolated from the leaves of Artemisia annua [3,4,5,6,7,8]. Due to its very high antimalarial activities, artemisinin, its derivatives, and numerous analogs have become important as antimalarial drugs against multidrug-resistant forms of Plasmodium falciparum [9]. Recently, numerous reports have also described diverse antitumor activities of these compounds [10,11,12,13,14]. This high pharmacological potential combined with its synthetically challenging and chemically unusual structure have prompted synthetic chemists to design total or partial synthesis routes to this compound and derivatives thereof [15,16,17,18,19,20,21,22] as well as the design of artemisinin dimers, conjugates and dyads [23]. In addition, flow chemistry has been applied in order to produce large amounts of artemisinin involving a photochemical key step [24,25,26]. With respect to the chemical reactivity of artemisinin derivatives, an ongoing discussion concerns the correlation between biological activity and the kind of peroxide-related steps that actually interfere with parasite-infected cells [27,28,29,30].
The central pharmacophore of natural artemisinin and derivatives is the 1,2,4-trioxane ring. A more detailed look at the artemisinin structure shows that this group is part of a bicyclo[3.2.2]nonane skeleton, i.e., not existing in a perfect cyclohexane chair conformation. Furthermore, not only a peracetal group but also an acetal is present in artemisinin and its dihydroderivative (DHA, with a further hemiactal structure) or DHA ethers like arthemether or artheether (corresponding to the methyl and ethyl ether of DHA, respectively). A structural simplification that has been extensively realized synthetically and examined with respect to antimalaria-activity is the 3-spiroannelated 1,2,4-trioxane structure [31,32,33]. We have recently started to explore synthetic routes to these compounds as well as to ring-contracted bicyclic peroxides with intact 1,2,4-trioxane units as well as to multifunctional trioxanes [34,35,36]. Additionally, molecular dyads that combine the natural artemisinin skeleton with synthetic trioxanes were realized by our group [37,38,39]. The synthetic protocol that we follow in this approach is depicted in Scheme 1: allylic alcohols A are highly reactive substrates for the singlet oxygen ene reaction and lead to β-hydroxy hydroperoxides B with high regio- and, in the case of chiral allylic alcohols, also high threo diastereoselectivity. Furthermore, Broensted or Lewis acid (boron trifluoride shown as a representative example) catalyzed peroxyacetalization of B, in the presence of ketones, aldehydes (R3R4C=O) or equivalent reagents (acetals or orthoesters), did eventually result in the formation of the desired 1,2,4-trioxanes C.
From chiral 3,3-dimethylated substrates (R1=CH3), diastereoisomeric mixtures of threo and erythro oxygenation products are formed in ratios that are strongly solvent-dependent [40]. Arylated substrates (R1=Ar) result in even higher diastereoselectivities [41,42]. We have now envisaged combining this selectivity-enhancing effect with the synthesis of multifunctional 2,3,8-trioxabicyclo[3.3.1]nonanes F, perorthoesters with the core structure of the bioactive 1,2,4-trioxane ring. From a structural point of view (Scheme 2, D = artemisinine), the combination of an additional (per)acetal group with the trioxane ring E appears to be an interesting new structural feature affecting the pharmacological properties of these compounds.

2. Results and Discussion

The synthetic protocol for the synthesis of bicyclic perorthoesters G as shown in Scheme 3 requires the preparation of 1-hydroperoxy-2,4-diols that are, in turn, available from allylic alcohols H by singlet oxygen ene reactions. The route to the 1,3-diols 6a6c starts with the Horner–Wadsworth–Emmons olefination of aric ketones 1a1c and subsequent reduction of the Michael esters 2a2c with DIBAL-H or lithium aluminum hydride. The allylic alcohols 3a3c were oxidized with MnO2 to give the aldehydes 4a4c. Aldol reaction with ethylacetate resulted in the aldols 5a5c that were reduced to the 1,3-diols 6a6c. The synthesis of the allylic hydroperoxides 7a7c from the allylic alcohols 6 proceeded according to literature procedures published by us for solid state photooxygenation [32,33,34].
This photooxygenation showed very high syn (threo) selectivity due to the well-known allylic hydroxy effect [40]. The selectivity was even higher (>95:5) as for the standard substrate 1,3-dimethyl-2-buten-1-ol (mesitylol, dr 85:15 under these conditions) because only the methyl group in Z-geometry to the stereogenic hydroxyl-substituted center is active in hydrogen transfer (Scheme 4). This high selectivity was also reported by Singh and coworkers for arylated (mono) allylic alcohols [41,42]. The suprafacial approach of the highly electrophilic singlet oxygen that appears from the same side as the hydroxyl group is located, indicating a hydrogen bond interaction that stabilizes the transition state.
The allylic hydroperoxides 7 were suitable substrates for the final peroxyacetalization. As carbonyl reagents, orthoesters were used because three condensation steps are necessary for the formation of the bicyclic products 8. As a Broensted acid catalyst, pyridinium-p-toluenesulfonic acid (PPTS) was used, and the products were obtained in moderate yields (20%–44%). Only the anisyl derivative 8d was formed in low yields of 8%. Because of the high threo-diastereoselectivity of the singlet oxygen ene reaction, the products were formed as preferentially as one diastereoisomer with a pseudo-equatorial conformation of the substituent R1 (corresponding to the precursor with R*R*-configuration, Scheme 5). Antimalaria activities of these compounds were in the micromolar range [43]. The most active 1,2,4-trioxanes that we have obtained by analogous synthetic route showed in vitro activities against Plasmodium falciparum (K1 strain) in the 1–5 nM region [31], one order of magnitude higher than the perorthoesters 8.
In order to explore the synthetic limitations of the perorthoester synthesis, the condensation of β-hydroxy hydroperoxides with orthocarbonates was investigated. As a model compound, the allylic hydroperoxide 9 (available from the singlet oxygen reaction with mesitylol J) was used and treated with a substoechiometric amount of tetramethylorthocarbonate. The primary peroxyacetalization proceeded smoothly to give the perorthocarbonate 10 in 30%, but no further reactivity of 10 was detected (Scheme 6).
In recent publications, we have also demonstrated the new potential of cyclic peroxides from the 1,2,4-trioxane family to inhibit certain glutathione transferases (GSTs), an important class of detoxification enzymes that are upregulated by tumor cells [44,45]. In order to demonstrate the relevance of the central peroxide ring system, we designed the synthesis of a 1,3-dioxane 15 (Scheme 7) that is structurally related to the biologically active 1,2,4-trioxane 11 (pNP = 4-nitrophenyl) [44]. The key synthetic step was again a singlet oxygen ene reaction with the homoallylic alcohol 12. In situ reduction of the hydroperoxide 13 with Me2S and acetalization delivered the dioxane 15. No inhibition of hpGST could be determined for this compound, which accounts for the relevance of the peroxidic 1,2,4-trioxane ring in bioactive compounds.

3. Experimental Section

Infrared spectra were obtained using a Perkin-Elmer 1600 series FTIR spectrometer (Perkin-Elmer, Walluf, Germany) and are given in cm−1 units. Solid samples are measured as CsI or KBr discs while liquids are measured as neat between two NaCl plates; the 1H-NMR spectra were recorded on Bruker Avance 300, Bruker DPX 300 spectrometers (Bruker, Ettlingen, Germany) operating at 300 MHz, or on Bruker Avance 500 spectrometer (Bruker, Ettlingen, Germany) instruments operating at 500 MHz. Chemical shifts are reported as δ in ppm and the coupling constants J in Hz units. In all spectra, the solvent peaks were used as the internal standard. Solvents used are CDCl3 (δ = 7.24 ppm), DMSO-d6 (δ = 2.49 ppm), acetone-d6 (δ = 2.04 ppm), and MeOH-d4 (δ = 3.35, 4.78 ppm). Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; the 13C-NMR spectra were recorded either on a Bruker Avance 300 spectrometer instrument operating at 75 MHz or on a Bruker Avance 500 spectrometer instrument operating at 125 MHz; high resolution mass spectra (HR-MS) were recorded on a Finnigan MAT 900 spectrometer(Scientific Instrument Services, Ringoes, NJ, USA) and are measured for the molecular ion peak (M+); CHN-combustion analyses were measured using an Elementar Vario EL Instrument (Elementar, Langenselbold, Germany).

General Procedures (GP)

GP-1: Horner–Wadsworth–Emmons reaction. In a flame-dried 200 mL three-necked flask in a nitrogen atmosphere, sodium hydride (60% dispersion in oil) was washed with hexane and suspended in THF. Triethylphosphonoacetate was dropped to the suspension at 0 °C over 10 min and stirred at r.t. for 30 min. After that, a solution of the ketone in THF was added in 10 min and the reaction mixture heated to reflux for 10 h. After cooling to r.t., an aqueous NH4Cl solution was added and extracted with 4× diethylether. The organic phases were washed with brine and dried over Na2SO4. After solvent evaporation, the product was purified by column chromatography.
GP-2: Reduction with DIBAL-H (diisobutylaluminium hydride). A solution of DIBAL-H (1.5 M in toluene) was slowly added to a solution of the ester 2 in diethylether cooled to 0 °C and subsequently stirred at r.t. for 2 h. After dilution with diethylether (twice the solvent volume of the starting reaction) and cooling to 0 °C, saturated aqueous NaCl solution was added slowly, the pH was adjusted to 3 with 4 M HCl, and the aqueous phase was extracted with 3× diethylether. The organic phases were washed with brine and dried over Na2SO4. After solvent evaporation, the product was purified by column chromatography.
GP-3: Oxidation with MnO2. A suspension of MnO2 in a toluene solution of the alcohol 3 was stirred overnight at RT. Afterwards, the reaction mixtures were filtered over celite and the solvent was evaporated. The crude product was purified by column chromatography.
GP-4: Aldol reactions with ethyl acetate. A solution of n-BuLi in hexane (19.2 mmol, 2 M) was added at −78 °C to a solution of diisopropylamine (19.2 mmol) in 40 mL of THF. After stirring for 5 min, ethyl acetate (16 mmol) was added and the mixture stirred at −78 °C for 2 h. Afterwards, the aldehyde 4 in 10 mL of THF was added and stirred for 5 min, warmed to −20 °C and quenched with 20 mL of 1 N HCl. The aqueous phase was extracted with 3× diethylether. The organic phases were washed with brine and dried over Na2SO4. After solvent evaporation, the product was purified by column chromatography.
GP-5: Reduction of aldols with NaBH4. In a flame-dried 200 mL three-necked flask in a nitrogen atmosphere, the aldol was dissolved in THF, cooled to 0 °C and NaBH4 was added in one portion. Afterwards, a solution of iodine in THF was slowly added and the reaction mixture heated to reflux for 3 h. After cooling to RT, methanol was carefully added until a clear solution resulted, stirred for 30 min and the solvent evaporated. The colorless residue was dissolved in a 1:1 water-diethylether solvent mixture, stirred for 20 min, separated and the aqueous phase extracted with 3× diethylether. The organic phases were washed with brine and dried over Na2SO4. After solvent evaporation, the product was purified by column chromatography.
GP-6a: Photooxygenation under homogeneous conditions. The substrate (1 mmol) was dissolved in 30 mL of CCl4 and 3–5 mg (2–4 × 10−4 M) of the sensitizer TPP (meso-tetraphenylporphyrin) were added. The solution was cooled to 10 °C and irradiated with a white LED under oxygen atmosphere until complete conversion (TLC = thin layer chromatography control). Subsequently, the solvent was evaporated and the residue analyzed by NMR. The crude hydroperoxides were directly used for peroxyacetalization.
GP-6b: Photooxygenation under polymer matrix conditions. Commercially available polystyrene-divinylbenzene copolymer beads (2.5 g) are distributed over a Petri dish (19 cm diameter) and swollen by CH2Cl2 (20 mL). The substrate (ca. 10 mmol) and the nonpolar sensitizer (TPP or TTP, ca. 3–6 mg) in ethyl acetate (20 mL) are subsequently added and the excess solvent is evaporated by leaving the Petri dish in a well ventilated hood. The Petri dish is then covered with a glass plate and the sandy solid is irradiated with a halogen lamp or a sodium street lamp. The polymer beads are subsequently rinsed with ethanol (3 × 30 mL) and filtered (the beads are kept for regeneration and reuse). The solvent is evaporated under reduced pressure (caution: water bath temperature should not exceed 30 °C).
GP-7a: Peroxyacetalization to give bicyclic perorthoesters. To a stirred solution of the β-hydroxy hydroperoxide 7 (1 mmol) and 3 equivalents of an orthoester in dry CH2Cl2 (12 mL) was added at room temperature a catalytic amount of pyridinium-p-toluenesulfonic acid (PPTS) (ca. 10 mg) and the mixture was further stirred for about 12 h (overnight) at the same temperature. The reaction mixture was partitioned between CH2Cl2 and saturated NaHCO3 solution and the phases were separated. The aqueous phase was extracted with CH2Cl2 (3 × 30 mL) and the combined organic phases were washed with brine and water, and dried over Na2SO4. Solvent evaporation (caution: water bath temperature should not exceed 30 °C) followed by chromatographic purification afforded the bicyclic perorthoesters as pure products.
GP-7b: Peroxyacetalization to give monocyclic 1,2,4-trioxanes. To a stirred solution of the β-hydroxy hydroperoxide and 1.5 equivalents of the carbonyl component in dry CH2Cl2 (100 mL) was added at room temperature a catalytic amount of boron trifluoride etherate (ca. 0.2 mL) and the mixture was further stirred for about 12 h (overnight) at the same temperature. The reaction mixture was partitioned between CH2Cl2 and saturated NaHCO3 solution and the phases were separated. The aqueous phase was extracted with CH2Cl2 (3 × 30 mL) and the combined organic phases were washed with brine and water, and dried over Na2SO4. Solvent evaporation (caution: water bath temperature should not exceed 30 °C), followed by chromatographic purification, afforded the spiro-bistrioxanes as pure products.
(E)-Ethyl-3-phenylbut-2-enoate (2a) [46]. Following GP-1 (General Procedure 1), 1.61 g (13.4 mmol) of acetophenone (1a) and 6.86 g (34.6 mmol, 2.6 eq) of triethylphosphono acetate and 1.33 g (33.4 mmol, 2.5 eq) of sodium hydride in 40 mL THF were reacted. The product was purified by column chromatography (CH/Et2O = 9:1, Rf = 0.22) and isolated as yellow oil: 2.0 g, 10.5 mmol, 78%. 1H-NMR (300 MHz, CDCl3): δ (ppm) = 1.32 (t, 3H, J = 7.1 Hz, CH3CH2), 2.59 (d, 3H, J = 1.2 Hz, CH3CH=), 4.22 (q, 2H, J = 7.1 Hz, CH2CH3), 6.15 (d, 1H, J = 1.2 Hz, CH3CH=), 7.35–7.49 (m, 5H, Har.). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 14.3 (CH3CH2), 17.9 (CH3), 59.8 (CH3CH2), 117.1 (HC=C), 126.2 (Car.), 128.4 (Car.), 128.9 (Car.), 142.2 (Car.), 155.4 (CH3C=), 166.8 (C=O).
(E)-3-Phenylbut-2-enol (3a) [47]. Following GP-2 (General Procedure 2), 335 mg (1.76 mmol) of ester 2a was reduced with 3.52 mL DIBAL-H (3.52 mmol, 2 eq, 1H solution in hexane) in 16 mL of diethylether. The product 3a was purified by column chromatography (PE/Et2O 9:1, Rf = 0.12) and isolated as colorless oil: 170 mg, 1.23 mmol, 70%. 1H-NMR (300 MHz, CDCl3): δ (ppm) = 2.09 (s, 3H, CH3), 2.70 (br s, 1H, OH), 4.38 (d, 2H, J = 6.63 Hz, CH2OH), 6.01 (dt, 1H, J = 1.33 Hz, 6.63 Hz, HC=C), 7.33–7.46 (m, 5H, Har.). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 15.8 (CH3), 59.8 (CH2OH), 125.6 (Car.), 126.5 (HC=C), 127.0 (Car.), 128.1 (Car.), 137.3 (CH3C=) 142.8 (Car.).
(E)-3-Phenylbut-2-enal (4a) [48]. Following GP-3 (General Procedure 3), 1.50 g (10.1 mmol) of the alcohol 3a and 15 g of MnO2 in 250 mL of toluene were reacted. The product was purified by column chromatography (PE/Et2O = 1:1, Rf = 0.30) and isolated as colorless oil: 0.84 g, 5.7 mmol, 57%. 1H-NMR (300 MHz, CDCl3): δ (ppm) = 2.55 (s, 3H, J = 1.2 Hz, CH3), 6.39 (dq, 1H, J = 1.2 Hz, 7.8 Hz, HC=C), 7.35–7.55 (m, 5H, Har.), 10.17 (d, 1H, J = 7.8 Hz, CHO). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 16.2 (CH3), 126.1 (Car.), 127.1 (Car.), 128.2 (Car.), 128.6 (Car.), 129.9 (HC=C), 140.4 (Car.), 157.4 (CH3C=), 191.0 (CHO).
(E)-Ethyl-3-hydroxy-5-phenylhex-4-enoate (5a). Following GP-4 (General Procedure 4), 840 mg (5.7 mmol) of the aldehyde 4a and 0.3 mL (3.8 mmol) of ethyl acetate were reacted. The product 5a was purified by column chromatography (CH/Et2O 3:2, Rf = 0.35) and isolated as yellow oil: 604 mg, 2.6 mmol, 68%. 1H-NMR (300 MHz, CDCl3): δ (ppm) = 1.30 (t, 3H, J = 7.2 Hz, CH3CH2), 2.13 (d, 3H, J = 1.5 Hz, CH3), 2.38 (m, 2H, CH2), 3.18 (br, 1H, OH), 4.20 (q, 2H, J = 7.2 Hz, CH2CH3), 5.00 (m, 1H, CHOH), 5.82 (dd, 1H, J = 7.2 Hz, 1.2 Hz, C=CH), 7.34–7.41 (m, 5H, Har.). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 14.0 (CH3CH2), 16.2 (CH3), 41.5 (CH2), 60.3 (CH2CH3), 65.4 (CHOH), 125.7 (HC=C), 127.3 (Car.), 128.1 (Car.), 128.4 (Car.), 137.7 (C=CH), 142.6 (Car.), 172.1 (C=O). IR (Film): ν (cm−1) = 3402 (s), 2979 (m), 2928 (m), 1730 (s), 1646 (w), 1492 (w), 1369 (s), 1277 (s), 1157 (s), 1020 (s), 948 (m), 860 (m). MS (EI, 70 eV): m/z (%) = 216 (M+ − H2O, 7), 171 (4), 143 (74), 128 (100), 115 (53).
(E)-5-Phenylhex-4-ene-1,3-diol (6a). Following GP-5 (General Procedure 5), 600 mg (2.56 mmol) of the aldol 5a was reduced with 240 mg (6.4 mmol, 2.5 eq) of NaBH4 and 200 mg (0.78 mmol, 0.3 eq) of I2. The product was purified by column chromatography (Et2O, Rf = 0.45) and isolated as yellow solid: 396 mg, 2.1 mmol, 80%. 1H-NMR (300 MHz, CDCl3): δ (ppm) = 1.84 (m, 2H, CH2), 2.10 (s, 3H, CH3), 2.57 (br s, 2H, OH), 3.88 (m, 1H, CH2OH), 4.83 (m, 1H, CHOH), 5.00 (m, 1H, CHOH), 5.84 (dd, 1H, J = 1.2 Hz, 8.4 Hz, C=CH), 7.30–7.40 (m, 5H, Har.). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 15.9 (CH3), 38.7 (CH2), 60.4 (CH2OH), 68.1 (CHOH), 125.6 (HC=C), 127.0 (Car.), 128.0 (Car.), 130.3 (Car.), 136.1 (C=CH), 142.7 (Car.). IR (Film): ν (cm−1) = 3323 (s), 2943 (m), 2880 (m), 1492 (w), 1379 (s), 1121 (w), 1044 (s), 955 (m), 895 (w), 755 (s), 695 (s). MS (EI, 70 eV): m/z (%) = 177 (M+ − CH3, 9), 159 (177 − H2O, 4), 147 (M+ − OCH2CH3, 87), 129 (100), 115 (53).
(E)-4-Methoxyethyl-3-phenylbut-2-enoate (2b) [49]. Following GP-1, 2.00 g (13.4 mmol) of 4-methoxy acetophenone (1b) and 6.86 g (34.6 mmol, 2.6 eq) of triethylphosphono acetate and 1.33 g (33.4 mmol, 2.5 eq) of sodium hydride in 40 mL THF were reacted. The product was purified by column chromatography (CH/Et2O = 9:1, Rf = 0.24) and isolated as yellow oil: 2.3 g, 10.4 mmol, 77%. 1H-NMR (300 MHz, CDCl3): δ (ppm) = 1.31 (t, 3H, J = 7.2 Hz, CH3CH2), 2.56 (d, 3H, J = 1.2 Hz, CH3), 3.82 (s, 3H, CH3O), 4.20 (q, 2H, J = 7.2 Hz, CH3CH2), 6.11 (d, 1H, J = 1.2 Hz, C=CH), 6.89 (m, 2H, Har.), 7.45 (m, 2H, Har.). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 14.3 (CH3CH2), 17.6 (CH3), 55.3 (CH3O), 59.6 (CH3CH2), 113.8 (Car.), 115.3 (CH=C), 127.6 (Car.), 134.3 (Car.), 154.8 (CH=C), 160.4 (Car.), 167.0 (C=O). IR (Film): ν (cm−1) = 2979 (s), 2914 (m), 1709 (s), 1625 (w), 1603 (m), 1513 (s), 1344 (s), 1157 (m), 1082 (m). MS (EI, 70 eV): m/z (%) = 221 (M+, 15), 192 (M+ − CH2CH3, 12), 175 (M+ − OCH2CH3, 100), 148 (M+ − O=COH2CH3, 83). CHN-analysis: (C13H16O3, M = 220.11 g/mol)—calcd.: 70.89% C 7.32% H, found: 71.04% C 7.63% H.
(E)-3-(4-Methoxyphenyl)but-2-ene-1-ol (3b) [50]. Following GP-2, 2.00 g (10.5 mmol) of ester 2b was reduced with 21 mL DIBAL-H (21 mmol, 2 eq, 1 M solution in hexane) in 60 mL of diethylether. The product 3b was purified by column chromatography (PE/Et2O 9:1, Rf = 0.10) and isolated as colorless oil: 1.79 g, 10.1 mmol, 96%. 1H-NMR (300 MHz, CDCl3): δ (ppm) = 2.06 (s, 3H, CH3), 3.81 (s, 3H, CH3O), 4.35 (d, 2H, J = 6.9 Hz, CH2), 5.92 (dt, 1H, J = 1.2 Hz, 6.9 Hz, C=CH), 6.87 (m, 2H, Har.), 7.36 (m, 2H, Har.). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 16.0 (CH3), 55.3 (CH3O), 59.9 (CH2OH), 113.6 (Car.), 124.8 (C=CH), 126.8 (Car.), 135.3 (CH2=C), 137.3 (Car.), 158.9 (Car.).
(E)-3-(4-Methoxyphenyl)but-2-enal (4b) [51]. Following GP-3, 1.79 g (10.1 mmol) of the alcohol 4a and 18 g of MnO2 in 250 mL of toluene were reacted. The product was purified by column chromatography (PE/Et2O = 1:1, Rf = 0.28) and isolated as colorless oil: 1.79 g (6.9 mmol, 68%). 1H-NMR (300 MHz, CDCl3): δ (ppm) = 2.54 (s, 3H, CH3), 3.84 (s, 3H, CH3O), 6.38 (dd, 1H, J = 1.2 Hz, 7.8 Hz, C=CH), 6.93 (d, 2H, J = 9 Hz, Har.), 7.53 (d, 2H, J = 9 Hz, Har.), 10.15 (d, 1H, J = 7.8 Hz, CHO). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 16.0 (CH3), 55.4 (CH3O), 114.0 (Car.), 125.5 (C=CH), 127.8 (Car.), 132.4 (Car.), 156.9 (C=CH), 161.3 (Car.), 191.2 (CHO). IR (film): ν (cm−1) = 2957 (w), 2837 (m), 1649 (s), 1593 (s), 1506 (m), 824 (s).
(E)-Ethyl-3-hydroxy-5-(4-methoxyphenyl)hex-4-enoate (5b). Following GP-4, 325 mg (1.8 mmol) of the aldehyde 4b and 0.13 mL (1.25 mmol) of ethyl acetate were reacted. The product 5a was purified by column chromatography (PE/Et2O 1:1, Rf = 0.18) and isolated as yellow oil: 360 mg, 1.4 mmol, 77%. 1H-NMR (300 MHz, CDCl3): δ (ppm) = 1.28 (t, 3H, J = 7.2 Hz, CH3CH2O), 2.08 (s, 3H, CH3), 2.60 (m, 2H, CH2), 2.95 (br s, 1H, OH), 3.80 (s, 3H, CH3O), 4.18 (q, 2H, J = 7.2 Hz, CH3CH2O), 4.96 (m, 1H, CHO), 5.72 (dd, 1H, J = 0.9 Hz, 8.4 Hz, C=CH), 6.85 (d, 2H, J = 8.7 Hz, Har.), 7.33 (m, 2H, J = 8.7 Hz, Har.). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 14.1 (CH3CH2), 16.3 (CH3), 41.6 (CH2), 55.2 (CH3O), 60.7 (CH3CH2), 65.8 (CHOH), 113.6 (Car.), 126.7 (C=CH), 126.9 (Car.), 135.1 (Car.), 137.3 (C=CH), 159.0 (Car.), 172.3 (C=O). IR (Film): ν (cm−1) = 3429(s), 2982 (s), 2831(m), 1731 (m), 1606 (m), 1506 (s), 826 (s). MS (EI, 70 eV): m/z (%) = 264 (M+, 21), 249 (M+ − CH3, 12), 246 (M+ − H2O, 27), 177 (90), 159 (76), 135 (CH3O(C6H4)CHCH3, 100), 115 (39).
(E)-5-(4-Methoxyphenyl)hex-4-ene-1,3-diol (6b). Following GP-5, 175 mg (0.66 mmol) of the aldol 6a was reduced with 63 mg (1.65 mmol, 2.5 eq) of NaBH4 and 51 mg (0.22 mmol, 0.3 eq) of I2. The product was purified by column chromatography (CHCl3/MeOH 9:1, Rf = 0.27) and isolated as colorless solid: 140 mg, 0.63 mmol, 96%. 1H-NMR (300 MHz, CDCl3): δ (ppm) = 1.79 (m, 2H, CH2), 2.04 (s, 3H, CH3), 3.34 (br s, 2H, 2 × OH), 3.78 (s, 3H, OCH3), 3.84 (m, 2H, CH2OH), 4.77 (m, 1H, CHOH), 5.75 (dd, 1H, J = 1.2 Hz, 8.4 Hz, C=CH), 6.83 (d, 2H, J = 8.7 Hz, Har.), 7.32 (d, 2H, J = 8.7 Hz, Har.). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 16.0 (CH3), 38.8 (CH2), 55.1 (OCH3), 60.7 (CH2OH), 68.4 (CHOH), 113.5 (C=CH), 126.7 (Car.), 128.5 (Car.), 135.1 (Car.), 135.9 (C=CH), 158.8 (Car.). IR (Film): ν (cm−1) = 3332 (s), 2938 (s), 1605 (m), 1510 (s), 1245 (s), 1032 (s), 826 (m). MS (EI, 70 eV): m/z (%) = 222 (M+, 12), 204 (M+ − H2O, 11), 177 (C11H13O2+, 45), 159 (49), 135 (100), 115 (39).
(E)-3-(2-Naphthyl)but-2-enylacetate (2c) [52]. Following GP-1, 2.21 g (13.4 mmol) of acetonaphthone (1c) and 6.86 g (34.6 mmol, 2.6 eq) of triethylphosphono acetate and 1.33 g (33.4 mmol, 2.5 eq) of sodium hydride in 40 mL THF were reacted. The product was purified by column chromatography (CH/Et2O = 9:1, Rf = 0.39) and isolated as colorless solid, m.p. 45–46 °C, 2.5 g, 10.5 mmol, 80%. 1H-NMR (300 MHz, CDCl3): δ (ppm) = 1.36 (t, 3H, J = 7.2 Hz, CH3CH2), 2.71 (d, 3H, J = 1.2 Hz, CH3), 4.28 (q, 2H, J = 7.2 Hz, CH3CH2), 6.32 (d, 1H, J = 1.2 Hz, C=CH), 7.4–7.9 (m, 7H, Har.). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 14.3 (CH3), 17.8 (CH3), 59.8 (CH2CH3), 117.4 (C=CH), 123.9 (Car.), 125.8 (Car.), 126.4 (Car.), 126.6 (Car.), 127.5 (Car.), 128.1 (Car.), 128.4 (Car.), 133.0 (Car.), 133.4 (Car.), 139.3 (Car.), 155.1 (C=), 166.8 (C=O).
(E)-3-(2-Naphthyl)but-2-ene-1-ol (3c) [53]. Following GP-2, 2.50 g (10.5 mmol) of ester 2c was reduced with 1.11 g (29.2 mmol, 2.8 eq) of LiAlH4 in 16 mL of diethylether. The product 3c was purified by recrystallization from benzene/hexane (1:1) resulting in 1.34 g (6.7 mmol, 64%) of colorless crystals, m.p. 85–86 °C. 1H-NMR (300 MHz, CDCl3): δ (ppm) = 1.67 (br s, 1H, OH), 2.20 (s, 3H, CH3) 4.44 (t, 2H, J = 5.6 Hz, CH2OH), 6.15 (t, 1H, J = 6.7 Hz, C=CH), 7.41–7.90 (m, 7H, Har.). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 16.0 (CH3), 60.0 (CH2OH), 124.1 (Car.), 124.5 (Car.), 125.8 (Car.), 126.1 (Car.), 127.0 (Car.), 127.5 (Car.), 128.1 (Car.), 128.4 (Car.), 133.3 (C=CH), 137.6 (Car.), and 139.3 (C=CH).
(E)-3-(2-Naphthyl)but-2-enal (4c) [51]. Following GP-3, 1.29 g (6.5 mmol) of the alcohol 3c and 13 g of MnO2 in 250 mL of toluene were reacted. The product was purified by column chromatography (PE/Et2O = 1:1, Rf = 0.56) and isolated as colorless oil: 0.88 g, 4.5 mmol, 69%. 1H-NMR (300 MHz, CDCl3): δ (ppm) = 2.64 (s, 3H, CH3), 6.55 (d, 1H, J = 7.8 Hz, C=CH), 7.51–8.01 (m, 7H, Har.), 10.23 (d, 1H, J = 7.8 Hz, CHO). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 16.2 (CH3), 123.3 (Car.), 126.2 (Car.), 126.6 (Car.), 127.1 (Car.), 127.3 (Car.), 127.5 (Car.), 128.3 (Car.), 128.6 (Car.), 132.8 (Car.), 133.9 (C=CH), 137.4 (Car.), 157.1 (C=CH), 191.1 (CHO).
(E)-Ethyl-3-hydroxy-5-(2-naphthyl)hex-4-enoate (5c). Following GP-4, 875 mg (4.5 mmol) of the aldehyde 4c and 0.30 mL (3.8 mmol) of ethyl acetate were reacted. The product was purified by column chromatography (CH/Et2O 3:2, Rf = 0.38) and isolated as yellow oil: 470 mg, 1.65 mmol, 37%. 1H-NMR (300 MHz, CDCl3): δ (ppm) = 1.30 (t, 3H, J = 7.2 Hz, CH3CH2) 2.23 (s, 3H, CH3), 2.66 (m, 2H, CH2), 4.11 (q, 2H, J = 7.2 Hz CH3CH2), 5.04 (m, 1H, CHOH), 5.94 (d, 1H, J = 7.2 Hz, C=CH), 7.45–7.82 (m, 7H, Har.). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 14.2 (CH3), 16.4 (CH2CH3), 41.6 (CH2), 60.9 (CH2CH3), 65.7 (CHOH), 124.2 (Car.), 124.7 (Car.), 125.9 (Car.), 126.2 (C=CH2), 127.5 (Car.), 127.8 (Car.), 128.2 (Car.), 128.8 (Car.), 132.8 (Car.), 133.3 (Car.), 137.8 (C=CH2), 139.1 (Car.). IR (film): ν (cm−1) = 3418 (s), 3054 (m), 2979 (m), 1730 (s), 1369 (m), 1277 (m), 1158 (s), 1019 (s), 853 (m), 816 (s), 747(s). MS (EI, 70 eV): m/z (%) = 284 (M+, 7), 266 (M+ − H2O, 13), 196 (M+ − C(=O)OCH2CH3, 56), 179 (100), 155 (77), 128 (52).
(E)-5-(2-Naphthyl)hex-4-ene-1,3-diol (6c). Following GP-5, 470 mg (1.65 mmol) of the aldol 5c was reduced with 160 mg (4.13 mmol, 2.5 eq) of NaBH4 and 130 mg (0.5 mmol, 0.3 eq) of I2. The product was purified by column chromatography (CHCl3/MeOH 9:1, Rf = 0.23) and isolated as colorless solid: 300 mg, 1.24 mmol, 75%. 1H-NMR (300 MHz, CDCl3): δ (ppm) = 1.89 (m, 2H, CH2) 2.20 (s, 3H, CH3), 2.29 (br s, 2H, OH), 3.94 (m, 2H, CH2OH), 4.90 (m, 2H, CHOH), 6.00 (dd, 1H, J = 1.2 Hz, 7.2 Hz, C=CH), 7.25–7.82 (m, 7H, Har.). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 16.3 (CH3), 38.8 (CH2), 61.4 (CH2O), 69.2 (CHOH), 124.1 (Car.), 124.6 (Car.), 127.5 (Car.), 127.6 (Car.), 127.8 (Car.), 128.0 (Car.), 128.1 (Car.), 128.7 (Car.), 130.6 (C=CH), 133.3 (Car.), 136.9 (C=CH), 138.7 (Car.). IR (Film): ν (cm−1) = 3304 (s), 2921 (s), 2851 (m), 1420 (m), 1272 (m), 1046 (s), 904 (s), 854 (m), 815 (s), 727(s). MS (EI, 70 eV): m/z (%) = 242 (M+, 5), 192 (M+ − H2O, 5), 175 (M+ − OCH2CH3, 100), 148 (M+ − O=COH2CH3, 83). Tm = 38–39 °C (aus CHCl3).
(R*R*)-4-Hydroperoxy-5-phenylhex-5-ene-1,3-diol (7a). Following GP-6a, 100 mg (0.52 mmol) of the diol 6a and 2.5 mg of TPP in 30 mL of CCl4 was irradiated for 5 h (complete conversion). Evaporation of the solvent delivered the crude product. 1H-NMR (300 MHz, CDCl3): δ (ppm) = 1.83 (m, 2H, CH2), 3.54 (m, 2H, CH2O), 4.42 (d, 1H, J = 3.9 Hz, CHOO), 4.99 (m, 1H, CHO), 5.09 (dt, 2H, J = 1.2 Hz, 12.6 Hz, CH2=C), 7.30–7.60 (m, 5H, Har.). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 34.1 (CH2), 60.6 (CH2OH), 72.3 (CHOH), 91.3 (CHOOH), 118.0 (C=CH2), 126.9 (Car.), 128.0 (Car.), 128.5 (Car.), 139.5 (C=CH2), 144.9 (Car.).
(R*R*)-4-Hydroperoxy-5-(4-methoxyphenyl)hex-5-ene-1,3-diol (7b). Following GP-6a (General Procedure 6a), 126 mg (0.57 mmol) of the diol 6b and 4 mg of TPP in 30 mL of CCl4 was irradiated for 5 h (37% conversion). Evaporation of the solvent delivered the crude product as a mixture of diastereoisomers (dr 95:5). 1H-NMR (300 MHz, CDCl3): δ (ppm) = 1.67 (m, 2H, CH2), 3.74 (s, 3H, OCH3), 3.88 (m, 2H, CH2O), 4.26 (d, 1H, J = 3.5 Hz, CHOO), 4.62 (m, 1H, CHO), 5.14 (d, 2H, J = 12.3 Hz, CH2=C), 6.7–7.4 (m 4H, Car.).
(R*R*)-4-Hydroperoxy-5-(2-naphthyl)hex-5-ene-1,3-diol (7c). Following GP-6b (General Procedure 6b), 200 mg (0.83 mmol) of the diol 6c was irradiated for 5h (40% conversion). Evaporation of the solvent delivered the crude product. 1H-NMR (300 MHz, CDCl3): δ (ppm) = 1.89 (m, 2H, CH2) 3.97 (m, 2H, CH2OH), 4.34 (m, 1H, CHOO), 4.65 (m, 2H, CHOH), 5.81 (m, 2H, C=CH2), 7.25–7.82 (m, 7H, Har.). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 35.8 (CH2), 60.2 (CH2O), 69.8 (CHOH), 124.1 (Car.), 124.6 (Car.), 127.5 (Car.), 127.6 (Car.), 127.8 (Car.), 128.0 (Car.), 128.1 (Car.), 128.7 (Car.), 129.4 (C=CH2), 133.3 (Car.), 138.7 (Car.), 139.7 (C=CH2).
(R*R*)-1-Methyl-4-(1-phenylvinyl)-2,3,8,9-tetraoxabicyclo[3.3.1]nonane (8a). Following GP-7a (General Procedure 7a), 224 mg (0.5 mmol) of the hydroperoxide 7a was reacted with 0.08 mL (1.5 mmol, 3 eq) of trimethyl orthoacetate and catalytic amounts of PPTS in 6 mL of dichloromethane. The product was purified by column chromatography (PE/Et2O 9:1, Rf = 0.43) and isolated as colorless oil (dr 94:6): 57 mg (0.23 mmol, 46%). 1H-NMR (300 MHz, CDCl3): δ (ppm) = 1.50 (s, 3H, CH3), 1.74 (m, 1H, CH2), 2.45 (m, 2H, CH2), 3.94 (m, 1H, CH2O), 4.21 (d, 1H, J = 6.3 Hz, CHO), 4.74 (m, 1H, CH2O), 4.95 (s, 1H, CHOO), 5.58 (s, 1H, C=CH2), 5.73 (s, 1H, C=CH2), 7.35 (m, 5H, Har.). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 24.1 (CH3), 27.5 (CH2), 60.0 (CH2O), 65.7 (CHO), 82.4 (CHOO), 113.5 (OCOO), 117.4 (C=CH2), 126.9 (Car.), 127.9 (Car.), 128.5 (Car.), 139.2 (Car.), 144.2 (C=CH2). IR (Film): ν (cm−1) = 2962 (m), 2923 (m), 2853 (m), 1493 (w), 1442 (m), 1380 (s), 1256 (s), 1105 (s), 966 (m), 900 (m), 752 (s), 702 (s).
(R*R*)-1-Ethyl-4-(1-phenylvinyl)-2,3,8,9-tetraoxabicyclo[3.3.1]nonane (8b). Following GP-7a, 224 mg (0.5 mmol) of the hydroperoxide 7a was reacted with 0.08 mL (1.5 mmol, 3 eq) of triethyl orthopropionate and catalytic amounts of PPTS in 6 mL of dichloromethane. The product was purified by column chromatography (PE/Et2O 4:1, Rf = 0.38) and isolated as colorless oil (dr 95:5): 27 mg (0.10 mmol, 21%). 1H-NMR (300 MHz, CDCl3): δ (ppm) = 1.00 (t, 3H, J = 7.5 Hz, CH3CH2), 1.75 (m, 3H, CH3CH2, CH2), 2.44 (m, 1H, CH2), 3.91 (m, 1H, CH2O), 4.21 (d, 1H, J = 6.6 Hz, CHO), 4.68 (m, 1H, CH2O), 4.96 (s, 1H, CHOO), 5.57 (s, 1H, C=CH2), 5.71 (s, 1H, C=CH2), 7.35 (m, 5H, Har.). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 6.7 (CH3CH2), 27.8 (CH2), 30.8 (CH3CH2), 59.6 (CH2O), 65.8 (CHO), 82.9 (CHOO), 114.7 (OCOO), 117.6 (C=CH2), 127.0 (Car.), 128.0 (Car.), 128.5 (Car.), 139.1 (Car.), 144.4 (C=CH2). IR (Film): ν (cm−1) = 2975 (m), 1493 (w), 1360 (m), 1250 (s), 1105 (s), 914 (s), 777 (s), 702 (s).
(R*R*)-4-(1-Phenylvinyl)-1-propyl-2,3,8,9-tetraoxabicyclo[3.3.1]nonane (8c). Following GP-7a, 224 mg (0.5 mmol) of the hydroperoxide 7a was reacted with 0.24 mL (1.5 mmol, 3 eq) of trimethyl orthobutyrate and catalytic amounts of PPTS in 6 mL of dichloromethane. The product was purified by column chromatography (PE/Et2O 4:1, Rf = 0.48) and isolated as colorless oil (dr 97:3): 39 mg (0.14 mmol, 28%). 1H-NMR (300 MHz, CDCl3): δ (ppm) = 0.92 (t, 3H, J = 7.5 Hz, CH3CH2), 1.54 (m, 2H, CH3CH2), 1.71 (m, 3H, CH3CH2CH2, CH2), 2.42 (m, 1H, CH2), 3.21 (m, 1H, CH2O), 4.21 (dd, 1H, J = 1.8 Hz, 6.6 Hz, CHO), 4.68 (m, 1H, CH2O), 4.96 (s, 1H, CHOO), 5.57 (s, 1H, C=CH2), 5.71 (s, 1H, C=CH2), 7.35 (m, 5H, Har.). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 14.0 (CH3CH2), 15.7 (CH3CH2CH2), 27.8 (CH2), 39.6 (CH3CH2), 59.6 (CH2O), 65.6 (CHO), 82.8 (CHOO), 114.4 (OCOO), 117.5 (C=CH2), 126.9 (Car.), 127.9 (Car.), 128.5 (Car.), 139.1 (Car.), 144.4 (C=CH2). IR (Film): ν (cm−1) = 2963 (s), 2928 (s), 2872 (s), 1732 (m), 1493 (w), 1378 (m), 1247 (s), 1119 (s), 928 (s), 777 (s), 701 (s).
(R*R*)-4-(1-(4-Methoxyphenyl)vinyl)-1-methyl-2,3,8,9-tetraoxabicyclo[3.3.1]nonane (8d). Following GP-7a, 120 mg (0.54 mmol) of the hydroperoxide 7b was reacted with 0.21 mL (1.62 mmol, 3 eq) of triethyl orthoacetate and catalytic amounts of PPTS in 6 mL of dichloromethane. The product was purified by column chromatography (PE/Et2O 4:1, Rf = 0.34) and isolated as colorless oil: 14 mg (0.05 mmol, 9%). 1H-NMR (300 MHz, CDCl3): δ (ppm) = 1.39 (s, 3H, CH3), 1.70 (m, 1H, CH2), 2.45 (m, 1H, CH2), 3.70 (s, 3H, CH3O), 3.82 (m, 1H, CH2O), 4.09 (dt, 1H, J = 1.9 Hz, 6.3 Hz, CHO), 4.61 (m, 1H, CH2O), 4.83 (s, 1H, CHOO), 5.40 (s, 1H, C=CH2), 5.51 (s, 1H, C=CH2), 6.76 (d, 2H, J = 8.8, Har.), 7.22 (d, 2H, J = 8.8 Hz, Har.). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 24.1 (CH3), 27.8 (CH2), 55.3 (CH3O) 59.8 (CH2O), 65.8 (CHO), 82.6 (CHOO), 113.6 (OCOO), 113.9 (Car.), 116.2 (C=CH2), 128.0 (Car.), 131.3 (Car.), 143.5 (C=CH2), 159.3 (Car.). IR (Film): ν (cm−1) = 2961 (s), 1606 (m), 1510 (s), 1464 (w), 1380 (m), 1246 (s), 1107 (m), 966 (m), 835 (s), 804 (m), 744 (w).
(R*R*)-1-Methyl-4-(1-(2-naphthyl)vinyl)-2,3,8,9-tetraoxabicyclo[3.3.1]nonane (8e). Following GP-7a, 220 mg (0.8 mmol) of the hydroperoxide 7c was reacted with 0.21 mL (1.62 mmol, 2 eq) of triethyl orthoacetate and catalytic amounts of PPTS in 8 mL of dichloromethane. The product was purified by column chromatography (PE/Et2O 4:1, Rf = 0.36) and isolated as colorless oil (dr 95:5): 50 mg (0.17 mmol, 20%). 1H-NMR (300 MHz, CDCl3): δ (ppm) = 1.49 (m, 1H, CH2), 1.75 (s, 3H, CH3), 2.28 (m, 1H, CH2), 3.91 (m, 1H, CH2O), 4.29 (m, 1H, CH2O), 4.36 (s, 1H, CHO), 5.28 (s, 1H, CHOO), 5.51 (s, 1H, C=CH2), 5.58 (s, 1H, C=CH2), 7.41–7.80 (m, 7H, Har.). 13C-NMR (75 MHz, CDCl3): δ (ppm) = 22.4 (CH3), 28.1 (CH2), 58.8 (CH2O), 76.9 (CHO), 80.0 (CHOO), 113.7 (OCOO), 120.1 (C=CH2), 124.7 (Car.), 124.8 (Car.), 126.2 (Car.), 126.4 (Car.), 127.6 (Car.), 128.0 (Car.), 128.3 (Car.), 132.9 (Car.), 133.2 (Car.), 136.1 (Car.), 145.8 (C=CH2). IR (film): ν (cm−1) = 3054 (m), 2966 (m), 2925 (m), 1731 (m), 1397 (s), 1300 (s), 1120 (s), 1012 (s), 942 (m), 855 (s), 750 (m). MS (EI, 20 eV): m/z (%) = 282 (M+ − CH3, 5), 266 (M+ − O2, 2), 240 (M+ − O2CCH3, 30), 222 (M+ − CH3CO3, 22), 195 (27), 184 (Naphthyl − C(CH2CH3)=CH2, 82), 165 (Naphthyl − C(=CH2)CH3, 57), 155 (Naphthyl − C=CH2, 100). 141 (Naphthyl − CH2, 27), 128 (Naphthyl, 27), 75 (CH3CO3, 56), 57 (CH3CO2, 89).
3,3-Dimethoxy-5-methyl-6-(1-propen-2-yl)-1,2,4-trioxane (10). Following the general procedure GP-6, 60 mg (0.45 mmol, 1.0 eq) of the hydroperoxide threo-9, 62 mg (0.03 mL, 0.23 mmol, 0.5 eq) of tetramethoxymethane and 12 mg (0.045 mmol, 0.1 eq) PPTS were reacted to give 28 mg (0.14 mmol, 30%) of the trioxane 10 after column chromatography (c-Hex/EtOAc (1:1), Rf = 0.85; 1H-NMR (300 MHz, CDCl3): δ (ppm): 1.17 (d, 3H, 3J = 6.0 Hz, O-CH-CH3), 1.77 (s, 3H, C-CH3), 3.44/3.49 (s, 2 × 3H, O-CH3), 4.26 (d, 1H, 3J = 8.6 Hz, C-CH-OO), 4.28–4.37 (m, 1H, CH3-CH-O), 4.13/4.30 (d, 1H, 3J = 8.6 Hz, CH-OOH). 5.13 (s, 2H, C=CH2); 13C-NMR (75.5 MHz, CDCl3): δ (ppm): 16.2 (q, 1C, O-CH-CH3), 19.5 (q, 1C, C-CH3), 51.4/52.3 (q, 2C, C-O-CH3), 71.0 (d, 1C, CH3-CH-O), 87.5 (d, 1C, C-CH-OOH), 118.7 (t, 1C, C-CH2), 137.0 (s, 1C, C=CH2). CHN-analysis: C12H22O3, (M = 214.30 g/mol), calcd. C 67.26% H 10.35% found: C 66.91% H 9.68%.
Methyl-5-hydroxy-2-methylpent-2-enonate (12). A mixture of 0.47 mL of propane-1,3-diol (0.5 g, 6.57 mmol) and 5.0 g of the ylene Methyl-2-(triphenylphosphoranyliden)propanoate [54] was dissolved in 17 mL of dichloromethane and 10.4 g of activated MnO2 were added. The mixture was stirred for 3 days at r.t. and filtered. The solid residue was washed with methylene chloride and, after solvent evaporation, purified by column chromatography (hexane/EtOAc 1:4, Rf = 0.52) to give 447 mg (3.10 mmol, 47%) 12 as a yellow oil. 1H-NMR (300 MHz, CDCl3): δ = 1.81 (s, 3H), 2.40 (q, J = 6.7 Hz, 2H), 3.68 (m, 5H), 6.74 (t, J = 7.3 Hz, 1H); 13C-NMR (75 MHz, CDCl3): δ = 12.6 (q), 32.1 (t), 51.9 (q), 61.2 (t), 129.6 (s), 138.7 (d), 168.6 (s).
Methyl 3,5-dihydroxy-2-methylenpentanoate (14). A chloroform solution of the hydroperoxide 13 (1.93 g, 10.9 mmol), obtained from the photooxygenation of the homoallylic alcohol 12 (following GP-6a), was treated with 16.5 mL of dimethylsulfide (13.9 g, 223 mmol) and stirred for 18h. After solvent and excess reagent evaporation, the residue was purified by column chromatography (CH/EtOAc 2:3, Rf = 0.30) to give 397 mg (2.25 mmol, 21%) 14 as a colorless oil. 1H-NMR (300 MHz, CDCl3): δ = 1.66 (m, 1H), 1.84 (m, 1H), 3.68 (m, 5H), 4.61 (dd, J = 3.1; 8.5 Hz, 1H), 5.86 (s, 1H), 6.19 (s, 1H); 13C-NMR (75 MHz, CDCl3): δ = 37.7 (t), 51.9 (q), 60.5 (t), 69.6 (d), 125.1 (t), 142.5 (s), 166.8 (s).
Methyl-2-(2-(4-nitrophenyl)-1,3-dioxan-4-yl)acrylate (15). A mixture of 711 mg of the diol 14 (4.00 mmol) and 737 mg of 4-nitrobenzaldehyde (4.80 mmol) in 38 mL of dry CH2Cl2 was treated with a stoechiometric amount (0.5 mL) of BF3 × Et2O and stirred for 18 h at r.t. After addition of 5 mL of aqueous Na2CO3, extraction with diethyl ether and solvent evaporation, the residue was purified by column chromatography (CH/EtOAc 3:1, Rf = 0.45) to give 346 mg (1.18 mmol, 49%) 15 as a yellowish solid, mp 99 °C; 1H-NMR (300 MHz, CDCl3): δ = 1.72 (dd, J = 12.0, 4.7 Hz, 1H), 1.86 (t, J = 21.2 Hz, 1H), 3.72 (s, 3H), 4.01 (t, J = 11.8 Hz, 1H), 4.24 (dd, J = 11.4, 4.5 Hz, 1H), 4.73 (d, J = 10.6 Hz, 1H), 5.64 (s, 1H), 5.95 (s, 1H), 6.28 (s, 1H), 7.61 (d, J = 8.3 Hz, 2H), 8.14 (d, J = 8.4 Hz, 2H); 13C-NMR (75 MHz, CDCl3): δ = 31.9 (t), 52.1 (q), 67.3 (t), 75.0 (d), 99.8 (d), 123.5 (d), 125.8 (t), 127.3 (d), 140.1 (s), 145.0 (s), 148.2 (s), 165.8 (s); IR: ν (cm−1) = 1031 (s), 1093 (s), 1118 (s), 1215 (s), 1273 (m), 1292 (m), 1345 (s), 1437 (m), 1520 (s), 1607 (m), 1630 (m), 1933 (w), 2858 (w), 2951 (w); CHN analysis (C14H15NO6): calcd. C 57.34 H 5.16 N 4.78, found C 57.08 H 5.25 N 4.67.

Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie and the University of Cologne (network project).

Author Contributions

A.G.G. designed and coordinated the project and wrote the paper, M.B. performed the research on the 1,3-dioxane 15, M.K. performed the synthesis of the perorthocarbonate 10, A.R. performed the syntheses and studies of the cyclic peroxides 8a8e.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Tu, Y. Artemisinin—A gift from traditional medicine to the world (Nobel lecture). Angew. Chem. Int. Ed. 2015, 55, 10210–10226. [Google Scholar] [CrossRef] [PubMed]
  2. Tu, Y. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat. Med. 2011, 17, 10210–10226. [Google Scholar] [CrossRef] [PubMed]
  3. Linares, G.E.G.; Rodriguez, J.B. Current status and progresses made in malaria chemotherapy. Curr. Med. Chem. 2007, 14, 289–314. [Google Scholar] [CrossRef] [PubMed]
  4. Fidock, D.A.; Rosenthal, P.J.; Croft, S.L.; Brun, R.; Nwaka, S. Antimalarial drug discovery: Efficacy models for compound screening. Nat. Rev. Drug Discov. 2004, 3, 509–520. [Google Scholar] [CrossRef] [PubMed]
  5. Li, Y.; Wu, Y.-L. An over four millennium story behind qinghaosu (artemisinin)—A fantastic antimalarial drug from a traditional Chinese herb. Curr. Med. Chem. 2003, 10, 2197–2230. [Google Scholar] [CrossRef] [PubMed]
  6. Wiesner, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. New antimalarial drugs. Angew. Chem. Int. Ed. 2003, 42, 5274–5293. [Google Scholar] [CrossRef] [PubMed]
  7. Frederich, M.; Dogne, J.-M.; Angenot, L.; De Mol, P. New trends in anti-malarial agents. Curr. Med. Chem. 2002, 9, 1435–1456. [Google Scholar] [CrossRef] [PubMed]
  8. Klayman, D.L. Qinghaosu (artemisinin): An antimalarial drug from China. Science 1985, 228, 1049–1055. [Google Scholar] [CrossRef] [PubMed]
  9. Ansari, M.T.; Saify, Z.S.; Sultana, N.; Ahmad, I.; Saeed-Ul-Hassan, S.; Tariq, I.; Khanum, M. Malaria and artemisinin derivatives: An updated review. Mini-Rev. Med. Chem. 2013, 13, 1879–1901. [Google Scholar] [CrossRef] [PubMed]
  10. Crespo-Ortiz, M.P.; Wei, M.Q. Antitumor activity of artemisinin and its derivatives: From a well-known antimalarial agent to a potential anticancer drug. J. Biomed. Biotechnol. 2012, 2012, 247597. [Google Scholar] [CrossRef] [PubMed]
  11. Tan, W.; Lu, J.; Huang, M.; Li, Y.; Chen, M.; Wu, G.; Gong, J.; Zhong, Z.; Xu, Z.; Dang, Y. Anti-cancer natural products isolated from Chinese medicinal herbs. Chin. Med. 2011, 6, 27. [Google Scholar] [CrossRef] [PubMed]
  12. Firestone, G.L.; Sundar, S.N. Anticancer activities of artemisinin and its bioactive derivatives. Exp. Rev. Mol. Med. 2009, 11, e32. [Google Scholar] [CrossRef] [PubMed]
  13. Jeyadevan, J.P.; Bray, P.G.; Chadwick, J.; Mercer, A.E.; Byrne, A.; Ward, S.A.; Park, B.K.; Williams, D.P.; Cosstick, R.; Davies, J.; et al. Antimalarial and antitumor evaluation of novel C-10 non-acetal dimers of 10-(2-hydroxy-ethyl)deoxoartemisinin. J. Med. Chem. 2004, 47, 1290–1298. [Google Scholar] [CrossRef] [PubMed]
  14. Posner, G.H.; McRiner, A.J.; Paik, I.-H.; Sur, S.; Borstnik, K.; Xie, S.; Shapiro, T.A.; Alagbala, A.; Foster, B. Anticancer and antimalarial efficacy and safety of artemisinin-derived trioxane dimers in rodents. J. Med. Chem. 2004, 47, 1299–1301. [Google Scholar] [CrossRef] [PubMed]
  15. Chen, H.J.; Han, W.B.; Hao, H.D.; Wu, Y.K. A facile and scalable synthesis of qinghaosu (artemisinin). Tetrahedron 2013, 69, 1112–1114. [Google Scholar] [CrossRef]
  16. Yadav, J.S.; Thirupathaiah, B.; Srihari, P. A concise stereoselective total synthesis of (+)-artemisinin. Tetrahedron 2010, 66, 2005–2009. [Google Scholar] [CrossRef]
  17. Yadav, J.S.; Babu, R.S.; Sabitha, G. Total synthesis of (+)-artemisinin. Arkivoc 2003, 125–139. [Google Scholar]
  18. Zhou, W.-S.; Xu, X.-X. Total Synthesis of the Antimalarial Sesquiterpene Peroxide Qinghaosu and Yingzhaosu A. Acc. Chem. Res. 1994, 27, 211–216. [Google Scholar] [CrossRef]
  19. Liu, H.J.; Yeh, W.L.; Chew, S.Y. A total synthesis of the antimalarial natural product (+)-qinghaosu. Tetrahedron Lett. 1993, 34, 4435–4438. [Google Scholar]
  20. Avery, M.A.; Jennings-White, C.; Chong, W.K.M. Total synthesis of (+)-artemisinin and (+)-9-demethylartemisinin. Tetrahedron Lett. 1987, 28, 4629–4632. [Google Scholar] [CrossRef]
  21. Zhou, W.-S. Total synthesis of arteannuin (Qinghaosu) and related compounds. Pure Appl. Chem. 1986, 58, 817–824. [Google Scholar] [CrossRef]
  22. Schmid, G.; Hofheinz, W. Total synthesis of qinghaosu. J. Am. Chem. Soc. 1983, 105, 624–625. [Google Scholar] [CrossRef]
  23. Fröhlich, T.; Karagöz, A.C.; Reiter, C.; Tsogoeva, S.B. Artemisinin-derived dimers: potent antimalarial and anticancer agents. J. Med. Chem. 2016, 59, 7360–7388. [Google Scholar] [CrossRef] [PubMed]
  24. Gilmore, K.; Kopetzki, D.; Lee, J.W.; Horvath, Z.; McQuade, D.T.; Seidel-Morgenstern, A.; Seeberger, P.H. Continuous synthesis of artemisinin-derived medicines. Chem. Commun. 2014, 50, 12652–12655. [Google Scholar] [CrossRef] [PubMed]
  25. Kopetzki, D.; Levesque, F.; Seeberger, P.H. A continuous-flow process for the synthesis of artemisinin. Chem. Eur. J. 2013, 19, 5450–5456. [Google Scholar] [CrossRef] [PubMed]
  26. Levesque, F.; Seeberger, P.H. Continuous-flow synthesis of the anti-malaria drug artemisinin. Angew. Chem. Int. Ed. 2012, 51, 1706–1709. [Google Scholar] [CrossRef] [PubMed]
  27. Meunier, B.; Robert, A. Heme as trigger and target for trioxane-containing antimalarial drugs. Acc. Chem. Res. 2010, 43, 1444–1451. [Google Scholar] [CrossRef] [PubMed]
  28. Laurent, S.A.-L.; Robert, A.; Meunier, B. Comments on “Highly antimalaria-active artemisinin derivatives: biological activity does not correlate with chemical reactivity”. C10-modified artemisinin derivatives: Efficient heme-alkylating agents. Angew. Chem. Int. Ed. 2005, 44, 2060–2063. [Google Scholar] [CrossRef] [PubMed]
  29. Haynes, R. Reply to comments on “Highly antimalaria-active artemisinin derivatives: Biological activity does not correlate with chemical reactivity”. Angew. Chem. Int. Ed. 2005, 44, 2064–2065. [Google Scholar] [CrossRef]
  30. Wu, Y. How might qinghaosu (artemisinin) and related compounds kill the intraerythrocytic malaria parasite? A chemist’s view. Acc. Chem. Res. 2002, 35, 255–259. [Google Scholar] [CrossRef] [PubMed]
  31. Griesbeck, A.G.; El-Idreesy, T.T.; Höinck, L.-O.; Lex, J.; Brun, R. Novel spiro-anellated 1,2,4-trioxanes with high in vitro antimalarial activities. Bioorg. Med. Chem. Lett. 2005, 15, 595–597. [Google Scholar] [CrossRef] [PubMed]
  32. Griesbeck, A.G.; El-Idreesy, T.T.; Bartoschek, A. Photooxygenation in polymer matrices: en route to highly active antimalarial peroxides. Pure Appl. Chem. 2005, 77, 1059–1074. [Google Scholar] [CrossRef]
  33. Bartoschek, A.; El-Idreesy, T.T.; Griesbeck, A.G.; Höinck, L.-O.; Lex, J.; Miara, C.; Neudörfl, J.M. A family of new 1,2,4-trioxanes by photooxygenation of allylic alcohols in sensitizer-doped polymers and secondary reactions. Synthesis 2005, 2433–2444. [Google Scholar] [CrossRef]
  34. Griesbeck, A.G.; El-Idreesy, T.T.; Bartoschek, A. Photooxygenation in polystyrene beads with covalently and non-covalently bound tetraarylstyrene sensitizers. Adv. Synth. Catal. 2004, 346, 245–251. [Google Scholar] [CrossRef]
  35. Griesbeck, A.G.; Bartoschek, A. Sustainable Photochemistry: Solvent-Free Singlet Oxygen-Photooxygenation of Organic Substrates Embedded in Porphyrin-Loaded Polystyrene Beads. Chem. Commun. 2002, 1594–1595. [Google Scholar] [CrossRef]
  36. Griesbeck, A.G.; Höinck, L.-O.; Lex, J.; Neudörfl, J.; Blunk, D.; El-Idreesy, T.T. 1,2,5,10,11,14-Hexaoxadispiro[5.2.5.2]hexadecanes: Novel spirofused bis-trioxane peroxides. Molecules 2008, 13, 1743–1758. [Google Scholar] [CrossRef] [PubMed]
  37. Griesbeck, A.G.; Blunk, D.; El-Idreesy, T.T.; Raabe, A. Bicyclic peroxides and perorthoester with 1,2,4-trioxane structures. Angew. Chem. Int. Ed. 2007, 46, 8883–8886. [Google Scholar] [CrossRef] [PubMed]
  38. Griesbeck, A.G.; Neudörfl, J.; Hörauf, A.; Specht, S.; Raabe, A. Antimalarial peroxide dyads from natural artemisinin and hydroxyalkylated 1,2,4-trioxanes. J. Med. Chem. 2009, 52, 3420–3423. [Google Scholar] [CrossRef] [PubMed]
  39. Griesbeck, A.G.; Raabe, A. Peroxide Dyads from Natural Artemisinin and Synthetic Perorthoesters and Endoperoxides. Synlett 2009, 1514–1516. [Google Scholar] [CrossRef]
  40. Griesbeck, A.G.; Adam, W.; Bartoschek, A.; El-Idreesy, T.T. Photooxygenation of allylic Alcohols: Comparison of unfunctionalized alkenes, and acetates with prenol-type allylic alcoholes and acetates. Photochem. Photobiol. Sci. 2003, 2, 877–881. [Google Scholar] [CrossRef] [PubMed]
  41. Singh, C.; Gupta, N.; Puri, S.K. Synthesis of new 6-alkylvinyl/arylalkylvinyl substituted 1,2,4-trioxanes active against multidrug-resistant malaria in mice. Bioorg. Med. Chem. 2004, 12, 5553–5562. [Google Scholar] [CrossRef] [PubMed]
  42. Singh, C.; Malik, H.; Puri, S.K. Orally active amino functionalized antimalarial 1,2,4-trioxanes. Bioorg. Med. Chem. Lett. 2004, 14, 459–462. [Google Scholar] [CrossRef] [PubMed]
  43. Griesbeck, A.G.; Raabe, A.; Kim, H. Activities (EC50 vs. P. falciparum) of 20–35 μM were determined. unpublished results.
  44. Bräutigam, M.; Teusch, N.; Schenk, T.; Sheikh, M.; Aricioglu, R.Z.; Borowski, S.H.; Neudörfl, J.-M.; Baumann, U.; Griesbeck, A.G.; Pietsch, M. Selective inhibitors of glutathione transferase P1 with trioxane structure as anticancer agents. ChemMedChem 2015, 10, 629–639. [Google Scholar] [CrossRef] [PubMed]
  45. Griesbeck, A.G.; Maaβen, A.; Bräutigam, M.; Pietsch, M. Model studies on peroxidic glutathione transferase (GST) inhibitors: C5-methylated 1,2,4-trioxanes with C6-acrylate side chains. Eur. J. Org. Chem. 2015, 2015, 4349–4352. [Google Scholar] [CrossRef]
  46. Yilmaz, E.V.B.; Yilmaz, M.; Öktemer, A. Radical cyclizations of conjugated esters and amides with 3-oxopropanenitriles mediated by manganese(III)acetate. Arkivoc 2011, 2011, 363–376. [Google Scholar]
  47. Zhang, P.; Le, H.; Kyne, R.E.; Morken, J.P. Enantioselective construction of all-carbon quaternary centers by branch-selective Pd-catalyzed allyl-allyl cross-coupling. J. Am. Chem. Soc. 2011, 133, 9716–9718. [Google Scholar] [CrossRef] [PubMed]
  48. Pedrosa, R.; Andrés, C.; Nieto, J. Stereocontrolled IMDA reaction of styrene derivatives. A way to enantiopure 3a,4,9,9a-tetrahydrobenz[f]isoindolines. J. Org. Chem. 2002, 67, 782–789. [Google Scholar] [CrossRef] [PubMed]
  49. Attia, M.I.; Herdeis, C.; Bräuner-Osborne, H. GABA-Agonistic activity of certain baclofen homologues. Molecules 2013, 18, 10266–10284. [Google Scholar] [CrossRef] [PubMed]
  50. Nguyen, T.N.T.; Thiel, N.O.; Pape, F.; Teichert, J.F. Copper(I)-catalyzed allylic substitutions with a hydride nucleophile. Org. Lett. 2016, 18, 2455–2458. [Google Scholar] [CrossRef] [PubMed]
  51. Mou, C.; Zhu, T.; Zheng, P.; Yang, S.; Song, B.-A.; Chi, Y.R. Green and rapid access to benzocoumarins via direct benzene construction through base-mediated formal [4 + 2] reaction and air oxidation. Adv. Synth. Catal. 2016, 358, 707–712. [Google Scholar] [CrossRef]
  52. Deng, J.; Duan, Z.-C.; Huang, J.-D.; Hu, X.-P.; Wang, D.-Y.; Yu, S.-B.; Xu, X.-F.; Zheng, Z. Rh-catalyzed asymmetric hydrogenation of γ-phthalimido-substituted α,β-unsaturated carboxylic acid esters: An efficient enantioselective synthesis of β-aryl-γ-amino acids. Org. Lett. 2007, 9, 4825–4828. [Google Scholar] [CrossRef] [PubMed]
  53. Bernasconi, M.; Ramella, V.; Tosatti, P.; Pfaltz, A. Iridium-catalyzed asymmetric hydrogenation of 3,3-disubstituted allylic alcohols in ethereal solvents. Chem. Eur. J. 2014, 20, 2440–2444. [Google Scholar] [CrossRef] [PubMed]
  54. Eey, S.T.C.; Lear, M.J. A bismuth(III)-catalyzed Friedel–Crafts cyclization and stereocontrolled organocatalytic approach to (−)-platensimycin. Org. Lett. 2010, 12, 5510–5513. [Google Scholar] [CrossRef] [PubMed]
  • Sample Availability: Not Available.
Scheme 1. Synthetic route to 1,2,4-trioxanes using the singlet oxygen ene reaction.
Scheme 1. Synthetic route to 1,2,4-trioxanes using the singlet oxygen ene reaction.
Molecules 22 00119 sch001
Scheme 2. Artemisinin structure (solid lines indicating the relevant bicyclic peroxide structure), 1,2,4-trioxane and 2,3,8-bicyclo[3.3.1]nonane structures.
Scheme 2. Artemisinin structure (solid lines indicating the relevant bicyclic peroxide structure), 1,2,4-trioxane and 2,3,8-bicyclo[3.3.1]nonane structures.
Molecules 22 00119 sch002
Scheme 3. Synthesis of substrates for and products from singlet oxygen ene reactions with hydroxyethylated allylic alcohols 6.
Scheme 3. Synthesis of substrates for and products from singlet oxygen ene reactions with hydroxyethylated allylic alcohols 6.
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Scheme 4. Regio- and diastereoselectivity controlling elements in the singlet oxygen ene reaction with allylic alcohols 6.
Scheme 4. Regio- and diastereoselectivity controlling elements in the singlet oxygen ene reaction with allylic alcohols 6.
Molecules 22 00119 sch004
Scheme 5. Diastereoisomeric 2,3,8-trioxabicyclo[3.3.1]nonanes (R*R*-8 preferred over R*S*-8) and force field optimized model compound without aryl substituents.
Scheme 5. Diastereoisomeric 2,3,8-trioxabicyclo[3.3.1]nonanes (R*R*-8 preferred over R*S*-8) and force field optimized model compound without aryl substituents.
Molecules 22 00119 sch005
Scheme 6. Literature-known dimeric trioxane structure I [36] and envisaged synthetic approach to the hexaoxaspiro[5,5]undecane structure K.
Scheme 6. Literature-known dimeric trioxane structure I [36] and envisaged synthetic approach to the hexaoxaspiro[5,5]undecane structure K.
Molecules 22 00119 sch006
Scheme 7. Antitumor-active 1,2,4-trioxane 11 and synthetic route to the non-peroxidic 1,3-dioxane 15.
Scheme 7. Antitumor-active 1,2,4-trioxane 11 and synthetic route to the non-peroxidic 1,3-dioxane 15.
Molecules 22 00119 sch007
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