Next Article in Journal
Enhanced Physical and Mechanical Properties of Nitrile-Butadiene Rubber Composites with N-Cetylpyridinium Bromide-Carbon Black
Next Article in Special Issue
Solar Photooxygenations for the Manufacturing of Fine Chemicals—Technologies and Applications
Previous Article in Journal
Spin Hamiltonians in Magnets: Theories and Computations
Previous Article in Special Issue
New Photochromic α-Methylchalcones Are Highly Photostable, Even under Singlet Oxygen Conditions: Breaking the α-Methyl Michael-System Reactivity by Reversible Peroxybiradical Formation
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 26
Issue 4
10.3390/molecules26040804
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Stereoselective [4+2] Cycloaddition of Singlet Oxygen to Naphthalenes Controlled by Carbohydrates

by
Marcel Bauch
,
Werner Fudickar
and
Torsten Linker
*
Department of Chemistry, University of Potsdam, Karl-Liebknecht-Street 24-25, 14476 Golm, Germany
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(4), 804; https://doi.org/10.3390/molecules26040804
Submission received: 13 January 2021 / Revised: 22 January 2021 / Accepted: 2 February 2021 / Published: 4 February 2021
(This article belongs to the Special Issue Singlet Oxygen-Photooxygenation of Organic Compounds)
Browse Figures
Versions Notes

Abstract

:
Stereoselective reactions of singlet oxygen are of current interest. Since enantioselective photooxygenations have not been realized efficiently, auxiliary control is an attractive alternative. However, the obtained peroxides are often too labile for isolation or further transformations into enantiomerically pure products. Herein, we describe the oxidation of naphthalenes by singlet oxygen, where the face selectivity is controlled by carbohydrates for the first time. The synthesis of the precursors is easily achieved starting from naphthoquinone and a protected glucose derivative in only two steps. Photooxygenations proceed smoothly at low temperature, and we detected the corresponding endoperoxides as sole products by NMR. They are labile and can thermally react back to the parent naphthalenes and singlet oxygen. However, we could isolate and characterize two enantiomerically pure peroxides, which are sufficiently stable at room temperature. An interesting influence of substituents on the stereoselectivities of the photooxygenations has been found, ranging from 51:49 to up to 91:9 dr (diastereomeric ratio). We explain this by a hindered rotation of the carbohydrate substituents, substantiated by a combination of NOESY measurements and theoretical calculations. Finally, we could transfer the chiral information from a pure endoperoxide to an epoxide, which was isolated after cleavage of the sugar chiral auxiliary in enantiomerically pure form.

Graphical Abstract

1. Introduction

Singlet oxygen (1O2) is an excited state of molecular oxygen and has been used for various oxidations, in biology, or medical applications [1]. Although the lifetime of this reactive species is short [2], depending on the solvent [3] or the biological environment [4], it can react with high regio- [5] and stereoselectivity [6]. It was the pioneering work of Adam, who discovered that OH groups can control the diastereoselectivity in ene reactions [7,8] or [4+2] cycloadditions of 1O2 to naphthalenes [9,10]. Later on, the influence of other functional groups on photooxygenations has been investigated [6,11], and our group described the influence of acids and esters on ene reactions [12,13]. However, the enantioselective transfer of 1O2 is still challenging, because of its short lifetime. Although the α-hydroxylation of aldehydes and ketones was realized by organocatalysis with moderate to good ee (enantiomeric excess) [14,15,16], ene reactions or cycloadditions proceed less successfully. Thus, asymmetrically modified zeolites [17], chiral salts [18], or chiral sensitizers [19] afforded only low stereoselectivities. Best results with up to 90% ee have been obtained in photooxygenations of 2-pyridones in the presence of chiral bicyclic lactams, which, however, had to be used in excess [20].
Another possibility to control the face-selectivity of singlet oxygen attack are chiral auxiliaries. First attempts with oxazolines gave no selectivity [21], but menthol derivatives [22] or tartrates [23] showed moderate to good induction. Best results have been obtained with oxazolidines [24], sultams [25], and especially enecarbamates [26], all developed in the group of Adam [27]. However, to the best of our knowledge, carbohydrates have not served as chiral auxiliaries for the stereoselective transfer of 1O2 until now. Only sugar-furans have been photooxygenated, but the intermediary formed peroxides rearrange thermally and cannot be isolated [28,29,30].
Based on our experience in carbohydrate chemistry [31,32,33] and acene oxidations [34,35,36,37], we became interested in a combination of both research topics and in sugar-substituted naphthalenes 1 (Scheme 1). The advantage of such arenes is that they react with 1O2 by a [4+2] cycloaddition in high yields to endoperoxides (EPOs) 2, as pointed out with simple alkyl- [38] and methoxy-substituted [39] systems 1a (R1 = Alk, OMe). Furthermore, the EPOs 2a reconvert quantitatively to the parent naphthalene 1a under thermal conditions and under release of singlet oxygen [40,41,42]. We investigated the influence of substituents R2 on the kinetics of such reactions [43] and could establish an intramolecular transfer of 1O2 [44]. However, carbohydrate-substituted naphthalenes 1b–f were hitherto unknown, but will generate new stereogenic centers during the oxidation (Scheme 1). Herein, we describe the synthesis of such compounds, their photooxygenation, isolation of peroxides, release of singlet oxygen, and a transformation into an enantiomerically pure epoxide.

2. Results and Discussion

The synthesis of carbohydrate-substituted naphthalenes 1b–f started from 1,4-naphthoquinone (3b), an inexpensive and easily available precursor. Addition of alkyl radicals, generated by decarboxylation of acids 4, afforded substituted naphthoquinones 3c–f in moderate to good yields, in analogy to literature (Scheme 2) [45]. In situ reduction with sodium dithionite [46] gave the corresponding 1,4-dihydroxynaphthalenes 5, which were directly used for the next step without purification, because of their oxidation lability. Finally, Schmidt’s trichloroacetimidate 6 [47,48] gave best results for glycosylations, and the hitherto unknown glucose-substituted naphthalenes 1b–f were isolated in good yields as single β-anomers in analytically pure form.
We started the photooxygenations with unsubstituted naphthalene 1b (R = H). Thus, substrate 1b (123 mg, 0.15 mmol) and sensitizer tetraphenylporphyrin (TPP, 1.0 mg) were dissolved in CD2Cl2 (3.0 mL) on an NMR scale. Oxygen was slowly bubbled through the solution, which was irradiated externally with a sodium lamp (400 W) at room temperature. The progress of the reaction was followed by TLC and NMR (300 MHz, measurements for every 60 min), however, even after 6 h, no conversion was observed (Table 1, entry 1). This can be explained by a steric hindrance of the carbohydrate substituents, or by a reversible reaction of 1O2 with naphthalenes [40,41], which is especially fast with alkoxy groups [39]. Indeed, we repeated the reaction at −70 °C and obtained full conversion after 2 h and the sole formation of one endoperoxide (EPO) 2b, determined by NMR (500 MHz) at the same temperature (entry 2, for detailed NMR spectra see Supplementary Materials). The fact that the reaction is completely reversible was confirmed by thermolysis at different temperatures and by measurement of the reappearing naphthalene UV absorption band, which provided kinetic data. We determined a half lifetime of 2 min at 20 °C, explaining why no conversion was observed at room temperature. Furthermore, at least 68% of the oxygen released during thermolysis was in its singlet state, which we proved by trapping with tetramethylethylene, and which is in accordance to simple naphthalene EPOs [40]. However, first attempts to transfer 1O2 even enantioselectively to a prochiral acceptor failed.
After the successful oxidation of naphthalene 1b (Table 1, entry 2), we next investigated the photooxygenations of the alkyl-substituted derivatives 1c–f under the same conditions (entries 3–6). For all substrates, the conversion was complete after 2 h, and we observed EPOs 2c–f as sole products in the NMR of the crude reaction mixture at low temperature (for detailed NMR spectra, see Supplementary Materials). Again, thermolysis of all EPOs proceeded completely reversible, and the parent naphthalenes 1c–f were reisolated quantitatively. However, the half lifetimes differ depending on the substituents R. Thus, the tBu derivative 2f was stable at room temperature for several hours and the products could be isolated in analytically pure form by column chromatography (entry 6). The higher stability of EPOs with larger substituents is in accordance to our previous studies with achiral naphthalenes [43].
Besides the remarkable thermal stability of EPOs 2, we found an interesting influence of the substituents on the stereoselectivity of the photooxygenations (Table 1). For naphthalene 1b, the two arene planes are identical, and only one EPO 2b can be formed (entry 2). However, for all other substrates 1c–f, singlet oxygen can attack from two different faces, affording two diastereomers 1S,4R-2 and 1R,4S-2. Indeed, naphthalenes 1c–e reacted with high stereoselectivities of about 9:1 to the corresponding EPOs 2c–e (entries 3–5). Surprisingly, the selectivity drops with tBu-substituted naphthalene 1f completely, and EPOs 2f are formed almost as 1:1 mixture (Table 1, entry 6). On the other hand, the diastereomers could be easily separated by column chromatography, characterized in pure form, and used for further transformations (see below). As the glucose substituents provide the stereochemical information, their steric and electrostatic repulsion of 1O2 must be responsible for the selectivities, and thus, our concept of a carbohydrate-auxiliary-controlled photooxygenation has been realized.
The thermally labile peroxides 2c–e could not be separated or isolated by column chromatography, but the dr was unequivocally determined from the 1NMRs of the crude products at low temperature (Figure 1 for selected chemical shifts, see Supplementary Materials for complete spectra). Although carbohydrate signals overlap, arene and double bond protons give distinctive signals. For the single isomer 2b, we obtained only one signal set with the protons at the double bond giving two doublets at 6.94 and 7.16 ppm. For EPOs 2c–f, the two diastereomers 1S,4R-2 and 1R,4S-2 exhibit two different signal sets, i.e., the major isomer as marked red and the minor isomer as marked green (Figure 1b–e). Characteristic is the double doublet at 7.9 ppm for the major isomers, which is assigned as H8 and speaks for its close proximity to the carbohydrate ring ortho to the substituent R. On the other hand, this proton has a chemical shift of 7.6 ppm for the minor isomers (Figure 1, green), which is a remarkable difference.
To understand this behavior, to determine the absolute configurations, and to find a rationale for the stereoselectivities, we analyzed the two diastereomeric EPOs 2f, which we isolated in analytically pure form, in more detail by a combination of analytical and theoretical methods. Thus, we measured their NOESY spectra (Supplementary Materials), which gave distinctive cross-peaks (Figure 2). For both isomers, the anomeric proton of the carbohydrate in the 4-position is in close proximity to H3 and, therefore, to the double bond (marked green). On the other hand, only EPO 1S,4R-2f shows an NOE between the 6-OAc group of the sugar in the 1-position and H7 (marked blue), which is located far away in the benzene ring. Thus, this carbohydrate is pushed away by the sterically demanding tBu group under the arene ring. Additionally, this explains the downfield shift of H8 to 8 ppm for all main isomers 1S,4R-2c–f, resulting from the ring-oxygen of the carbohydrate. In contrast, in isomer EPO 1R,4S-2f, H8 shows a normal shift of 7.6 ppm and an NOE is only observed to the 2-OAc and not to the 6-OAc group (marked orange). In summary, we propose for the main isomers a conformation with the carbohydrate in the 1-position far away from the peroxide bridge, whereas for the minor isomer, this sugar is in close proximity to the newly formed stereocenter.
To further support the observed NOESY interactions, we conducted theoretical calculations at the B3LYP/6-31G* level (for details see Supplementary Materials). Thus, structures for both diastereomeric EPOs 1S,4R-2f and 1R,4S-2f were minimized (Figure 3). Indeed, for the main isomer, we find a close proximity of the 6-OAc group of the sugar in the 1-position and H7, which nicely is in accordance to the NOESY measurements (Figure 2). On the other hand, in EPO 1R,4S-2f, both carbohydrates are located in the plane of the peroxide bridge, again in good correlation to the NMR spectra.
Our structural assignment of the configurations and conformations of EPOs 2 might give an explanation for the observed stereoselectivities and influence of substituents as well (Figure 4). Thus, for starting materials 1c–f, the carbohydrate in the 1-position is pushed away by the substituent R, resulting in a downfield shift of H8 (see NMR data in the section Materials and Methods). The second carbohydrate in the 4-position is much closer to the reacting naphthalene ring and, therefore, shields the si face. Thus, singlet oxygen has to attack from the opposite face, passing by the R group. Although the discussion of rotamers for the explanation of stereoselectivities is a bit speculative, our mechanistic proposal nicely fits to the observed influence of substituents. For naphthalene 1b (R = H), no selectivity can result, but the photooxygenation of isomers 1c–e (R = Me, Et, iPr) provide good stereoselectivities (see Table 1). Only for starting material 1f (R = tBu), the selectivity drops remarkably, because 1O2 has to pass by this sterically demanding group, and therefore, both faces are shielded equally. The fact that the tBu (1f) and iPr (1e) derivatives react with such different selectivity is surprising, because their steric substituent constants are in the same range [49]. We explain this again by hindered rotations due to interactions with the carbohydrates. Thus, for R = iPr, the two methyl groups may point away from the sugar in the 1-position, whereas for R = tBu, one methyl group shields the upper plane (Figure 4). The fact that a tBu group gives remarkably different stereoselectivities than an iPr group was found in other auxiliary-controlled reactions as well [50].
Finally, because our structural assignment was hitherto only based on NOESY measurements and calculations, we wanted to determine the absolute configurations unequivocally. Thus, we selected EPO 1S,4R-2f, which we could isolate in analytically pure form, which may have the same configuration as all main isomers, and which is stable enough for further transformations. Epoxidation with m-chloroperoxybenzoic acid (MCPBA) in dichloromethane afforded a single diastereomer syn-7 as shown by the NMR of the crude product. This is in accordance to literature-known epoxidations of simple naphthalene EPOs [51] and can be explained by steric interactions and hydrogen bonding to the peroxide bridge. The epoxide syn-7 was isolated by column chromatography in 76% yield in analytically pure form (Scheme 3). Finally, the chiral carbohydrate auxiliaries could be removed by catalytic hydrogenation of the O–O bond, and naphthoquinone epoxide 2S,3R-8 was isolated in 63% yield, besides some decomposition products. Now, we could determine its absolute configuration unequivocally by comparison of the optical rotation with literature-known epoxide 2R,3S-8, which was synthesized from chiral hydroperoxides in 82% ee [52].
The fact that our epoxide is enantiomerically pure was confirmed by HPLC on a chiral phase (Figure 5, Section 3). First, we synthesized racemic epoxide 8 by direct oxidation of naphthoquinone 3f in analogy to literature [53]. This racemate gave two peaks, separated by 2 min retention time (A), and epoxide 2S,3R-8 gave a single peak (B). Therefore, we could use carbohydrates as chiral auxiliaries to control the photooxygenation of naphthalenes, isolate endoperoxides in pure form, and transfer the chirality to new stereogenic centers under cleavage of the auxiliary, obtaining an enantiomerically pure product.

3. Materials and Methods

3.1. Chemicals and Instrumentation

Melting points were determined using a Mel-Temp from Electrothermal. TLC was performed using TLC Silica gel 60 F254 aluminum sheets from Merck. 1H-NMR and 13C-NMR spectra were measured using a Bruker Avance 300 (300 MHz, 75 MHz) (Rheinstetten, Germany), a Bruker NEO 500 (500 MHz, 125 MHz) (Rheinstetten, Germany), or a Bruker Avance 600 (600 MHz, 150 MHz) NMR spectrometer (Rheinstetten, Germany). The solvents (CDCl3 or CD2Cl2) were used as standard for calibrating chemical shifts. Signals were assigned by two-dimensional methods (HSQC). IR spectra were recorded in KBr pellets using a Nicolet Avatar 370 FT-IR spectrometer (Madison, WI, USA) from Thermo Electron Corporation. Optical rotations were measured on a JASCO P-1020 digital polarimeter (Tokio, Japan) at 589 nm. Elemental analysis was performed on a Vario EL III elemental analyzer (Elementar, Langenselbold, Germany). HRMS spectra were measured at a GC-MS Trace DSX II spectrometer (Dreieich, Germany). UV spectra were recorded with an Analytik Jena Specord S600 spectrometer (Analytik Jena, Jena, Germany). HPLC was performed with a Chrom Tech, Chiral-AGP column (100 mm × 3.00 mm, 5 μm), eluent hexane/ethyl acetate 10:1. All starting materials were used as purchased without further purification. Trichloroacetimidate gluco-6 was synthesized according to the literature [54].

3.2. Synthesis of Naphthoquinones 3

According to the literature [45], 1,4-naphthoquinone 3b (3.95 g, 25 mmol) and the corresponding carboxylic acid 4 (50 mmol, 2 equiv.) were dissolved in a 1:1 mixture of dichloromethane and acetonitrile (100 mL). This mixture was added to a solution of silver nitrate (425 mg, 2.5 mmol) and ammonium persulfate (11.4 g, 50 mmol) in water (100 mL) at room temperature. The mixture was heated under reflux for 4 h, cooled to room temperature, and diluted with dichloromethane (100 mL), and the organic phases were separated. The aqueous phase was extracted with dichloromethane (3 × 50 mL), and the combined organic layers were washed with brine (300 mL) and dried over magnesium sulfate. The solvent was removed in vacuo, and the crude products were purified by column chromatography (PE/EtOAc 10:1) to obtain the naphthoquinones 3c–f in analytically pure form.
2-Methyl-1,4-naphthoquinone3c. Obtained as a yellow solid (1.76 g, 41%). m.p. = 106–108 °C. Rf = 0.23 (PE/EtOAc 10:1). 1H-NMR (500 MHz, CD2Cl2): δ = 2.16 (d, J = 1.6 Hz, 3H; CH3), 6.81 (q, J = 1.6 Hz, 1H; 3-H), 6.77 (t, J = 1.6 Hz, 1H; 3-H), 7.70–7.74 (m, 2H; 7-H, 6-H), 7.99–8.02 (m, 1H; H-5), 8.03–8.07 ppm (m, 1H; 8-H). 13C-NMR (125 MHz, CD2Cl2): δ= 16.5 (q; CH3), 126.2 (d; C-5), 126.6 (d; C-8), 132.6 (s; C-8a), 132.6 (s; C-4a), 133.9 (d; C-7), 134.0 (d; C-6), 135.9 (d; C-3), 148.5 (s; C-2), 185.2 (s; C-4), 185.8 ppm (s; C-1); IR (Film): v = 3656 (w), 3292 (w), 2956 (m), 2920 (m), 1621 (s), 1588 (m), 1464 (m), 1329 (m), 1300 (s), 1245 (m), 1143 (m), 1061 cm−1 (m). HRMS (GC-TOF): m/z Calcd for C11H8O2 [M+]: 172.0524; Found: 172.0533. Anal. Calcd for C11H8O2 (172.18): C 76.73, H 4.68; Found: C 77.01, H 4.73.
2-Ethyl-1,4-naphthoquinone3d. Obtained as a yellow solid (2.35 g, 50%). m.p. = 83–84 °C. Rf = 0.27 (PE/EtOAc 10:1). 1H-NMR (600 MHz, CD2Cl2): δ = 1.19 (t, J = 7.4 Hz, 3H; CH3), 2.59 (dq, J = 7.4, 1.6 Hz, 2H; CH2), 6.77 (t, J = 1.6 Hz, 1H; 3-H), 7.72–7.75 (m, 2H; 7-H, 6-H), 8.01–8.03 (m, 1H; H-5), 8.06–8.09 ppm (m, 1H; 8-H). 13C-NMR (150 MHz, CD2Cl2): δ = 12.0 (q; CH3), 23.0 (t; CH2), 126.2 (d; C-5), 126.7 (d; C-8), 132.5 (s; C-8a), 132.8 (s; C-4a), 133.9 (d; C-7), 134.0 (d; C-6), 134.3 (d; C-3), 153.5 (s; C-2), 185.5 (s; C-4), 185.5 ppm (s; C-1). IR (Film): v = 3668 (w), 3312 (w), 2973 (m), 2906 (m), 1661 (s), 1590 (m), 1458 (m), 1385 (m), 1327 (m), 1296 (s), 1250 (m), 1143 (m), 1057 cm−1 (m). HRMS (GC-TOF): m/z Calcd for C12H10O2 [M+]: 186.0681; Found: 186.0687. Anal. Calcd for C12H10O2 (186.21): C 77.40, H 5.41; Found: C 77.40, H 5.71.
2-iPropyl-1,4-naphthoquinone3e. Obtained as a yellow solid (3.21 g, 64%). m.p. = 43–44 °C. Rf = 0.34 (PE/EtOAc 10:1). 1H-NMR (600 MHz, CD2Cl2): δ = 1.19 (2d, J = 6.9 Hz, 6H; CH3), 3.22 (dsept, J = 6.9, 1.2 Hz, 1H; CH), 6.76 (d, J = 1.2 Hz, 1H; 3-H), 7.72–7.76 (m, 2H; 6-H, 7-H), 8.01–8.04 (m, 1H; H-5), 8.07–8.10 ppm (m, 1H; 8-H). 13C-NMR (150 MHz, CD2Cl2): δ = 21.7 (2q; CH3), 27.4 (d; CH), 126.1 (d; C-5), 126.8 (d; C-8), 132.3 (s; C-4a), 133.0 (s; C-8a), 133.0 (d; C-3), 133.9 (d; C-7), 134.0 (d; C-6), 157.5 (s; C-2), 185.1 (s; C-1), 185.8 ppm (s; C-4). IR (Film): v = 3660 (w), 3315 (w), 3071 (w), 2967 (m), 2873 (m), 1660 (s), 1594 (m), 1463 (w), 1379 (w), 1328 (m), 1299 (s), 1251 (s), 1130 (w), 1074 cm−1 (m). HRMS (GC-TOF): m/z Calcd for C13H12O2 [M+]: 200.0837; Found: 200.0832. Anal. Calcd for C13H12O2 (200.23): C 77.98, H 6.04; Found: C 77.84, H 5.94.
2-tButyl-1,4-naphthoquinone3f. Obtained as a yellow solid (3.89 g, 73%). m.p. = 66–67 °C. Rf = 0.42 (PE/EtOAc 10:1). 1H-NMR (600 MHz, CD2Cl2): δ = 1.36 (s, 9H; t-Bu), 6.83 (s, 1H; 3-H), 7.71 (ddd, J = 8.9, 7.4, 1.5 Hz, 1H; 6-H), 7.74 (ddd, J = 8.9, 7.4, 1.6 Hz, 1H; H-7), 8.00 (ddd, J = 7.4, 1.6, 0.6 Hz, 1H; H-5), 8.07 ppm (ddd, J = 7.4, 1.5, 0.6 Hz, 1H; 8-H). 13C-NMR (150 MHz, CD2Cl2): δ = 29.5 (q; t-Bu), 36.0 (s; t-Bu), 125.7 (d; C-5), 127.0 (d; C-8), 131.9 (s; C-4a), 133.6 (d; C-6), 134.0 (s; C-8a), 134.1 (d; C-7), 134.3 (d; C-3), 158.5 (s; C-2), 185.3 (s; C-1), 186.1 ppm (s; C-4). IR (Film): v = 3306 (w), 3071 (w), 2963 (m), 2910 (m), 2874 (m), 1792 (w), 1655 (s), 1594 (s), 1485 (m), 1460 (m), 1362 (m), 1331 (s), 1308 (s), 1249 (s), 1202 (m), 1127 cm−1 (s). HRMS (GC-TOF): m/z Calcd for C14H14O2 [M+]: 214.0994; Found: 214.0988. Anal. Calcd for C14H14O2 (214.26): C 78.48, H 6.59; Found: C 78.56, H 6.68.

3.3. Synthesis of Carbohydrate-Substituted Naphthalenes 1

In short, 1,4-Naphthoquinone 3 (5 mmol) was dissolved in EtOAc (15 mL) and an aqueous solution of sodium dithionite (2.61 g, 15 mmol, 15 mL) was added under nitrogen atmosphere at room temperature. After stirring for 3 h, the mixture was diluted with a saturated solution of ammonium chloride (15 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and dried over magnesium sulfate. The solvent was removed in vacuo, and the crude 1,4-dihydroxynaphthalene 5 was directly used for the next step.
The crude 1,4-dihydroxynapthalene 5 was dissolved in dry dichloromethane (50 mL), molecular sieves (4 Å), and a solution of trichloroacetimidate 6 (4.93 g, 10 mmol) in dry dichloromethane (50 mL) was added at room temperature. The mixture was cooled to −15 °C, and a solution of BF3·Et2O (0.13 mL, 1 mmol) in dry dichloromethane (5 mL) was added within 30 min. After stirring for 16 h at room temperature, the mixture was filtered over celite; washed with saturated solution of NaHCO3 (50 mL), water (50 mL), and brine (50 mL); and dried over magnesium sulfate. The solvent was removed in vacuo, and the crude products were purified by column chromatography (hexanes/EtOAc 1:1) to obtain the carbohydrate-substituted naphthalenes 1 in analytically pure form.
1,4-Bis-(1-O-2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)-naphthalene1b. Obtained as a colorless solid (2.923 g, 76%). m.p. = 169–171 °C. Rf = 0.18 (PE/EtOAc 1:1). [α ] D 24 = −67 (c 1.00, CHCl3). 1H-NMR (600 MHz, CD2Cl2): δ = 2.04 (2s, 6H; 3-OAc), 2.04 (2s, 6H; 4-OAc), 2.05 (2s, 6H; 2-OAc), 2.06 (2s, 6H; 6-OAc), 3.94 (2ddd, J = 10.0, 5.0, 2.5 Hz, 2H; 5-H), 4.20 (2dd, J = 12.3, 2.5 Hz, 2H; 6a-H), 4.32 (2dd, J = 12.3, 5.0 Hz, 2H; 6b-H), 5.21 (2dd, J = 10.0, 9.4 Hz, 2H; 4-H), 5.21 (2d, J = 7.9 Hz, 2H; 1-H), 5.36 (2dd, J = 9.7, 9.4 Hz, 2H; 3-H), 5.43 (2dd, J = 9.7, 7.9 Hz, 2H; 2-H), 7.02 (2s, 2H; 2-ArH, 3-ArH), 7.53–7.56 (m, 2H; 6-ArH, 7-ArH), 8.02–8.05 ppm (m, 2H; 5-ArH, 8-ArH). 13C-NMR (150 MHz, CD2Cl2): δ = 20.8 (4q; OAc-2, OAc-3), 20.9 (2q; OAc-6), 20.9 (2q; OAc-4), 62.2 (2t; C-6), 68.7 (2d; C-4), 71.4 (2d; C-2), 72.5 (2d; C-5), 72.8 (2d; C-3), 100.3 (2d; C-1), 109.7 (2d; ArC-2, ArC-3), 121.8 (2d; ArC-5, ArC-8), 126.9 (2s; ArC-4a, ArC-8a), 127.1 (2d; ArC-6, ArC-7), 149.0 (2s; ArC-1, ArC-4), 169.8 (2s; OAc-4), 169.9 (2s; OAc-2), 170.3 (2s; OAc-3), 170.7 ppm (2s; OAc-6). IR (Film): ν = 3024 (w), 2960 (w), 1746 (s), 1599 (w), 1371 (m), 1212 (s), 1122 (m), 1035 cm−1 (s). HRMS (ESI-Q-TOF): m/z Calcd for C38H44NaO20 [M + Na+]: 843.2324; Found: 843.2296. Anal. Calcd for C38H44O20 (820.75): C 55.61, H 5.40; Found: C 55.61, H 5.55.
2-Methyl-1,4-bis-(1-O-2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)-naphthalene1c. Obtained as a colorless solid (2.994 g, 72%). m.p. = 216–217 °C. Rf = 0.17 (PE/EtOAc 1:1). [α ] D 24 = −34 (c 1.00, CHCl3). 1H-NMR (600 MHz, CD2Cl2): δ = 1.88 (s, 3H; 6-OAc), 1.99 (s, 3H; 4-OAc), 2.03 (s, 3H; 2′-OAc), 2.03 (s, 3H; 3-OAc), 2.04 (s, 3H; 3′-OAc), 2.05 (s, 3H; 4′-OAc), 2.08 (s, 3H; 6′-OAc), 2.18 (s, 3H; 2-OAc), 2.46 (s, 3H; CH3), 3.56 (ddd, J = 10.0, 5.1, 2.6 Hz, 1H; 5-H), 3.98 (dd, J = 12.2, 2.6 Hz, 1H; 6a-H), 4.01 (ddd, J = 10.1, 5.8, 2.5 Hz, 1H, 5′-H), 4.17 (dd, J = 12.2, 5.1 Hz, 1H; 6b-H), 4.22 (dd, J = 12.3, 2.5 Hz, 1H; 6a′-H), 4.28 (dd, J = 12.3, 5.8 Hz, 1H; 6b′-H), 5.05 (d, J = 8.1 Hz, 1H; 1-H), 5.18 (dd, J = 10.0, 9.4 Hz, 1H; 4-H), 5.18 (dd, J = 10.1, 9.3 Hz, 1H; 4′-H), 5.26 (d, J = 7.8 Hz, 1H; 1′-H), 5.30 (dd, J = 9.8, 9.4 Hz, 1H; 3-H), 5.38 (dd, J = 9.8, 9.3 Hz, 1H; 3′-H), 5.44 (dd, J = 9.8, 8.1 Hz, 1H; 2-H), 5.45 (dd, J = 9.8, 7.8 Hz, 1H; 2′-H), 6.94 (s, 1H; 3-ArH), 7.44 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H; 6-ArH), 7.52 (ddd, J = 8.6, 6.8, 1.3 Hz, 1H; 7-ArH), 8.00 (ddd, J = 8.4, 1.3, 0.6 Hz, 1H; 5-ArH), 8.12 ppm (ddd, J = 8.6, 1.2, 0.6 Hz, 1H; 8-ArH). 13C-NMR (150 MHz, CD2Cl2): δ = 17.5 (q; CH3), 20.6 (q; OAc-6), 20.7 (q; OAc-4), 20.8 (q; OAc-2′), 20.8 (2q; OAc-2, OAc-3′), 20.9 (2q; OAc-4′, OAc-6′), 21.0 (q; OAc-2), 62.0 (t; C-6), 62.6 (t; C-6′), 68.8 (d; C-4), 68.9 (d; C-4′), 71.4 (d; C-2′), 72.1 (C-5), 72.2 (d; C-2), 72.5 (d; C-5′), 72.7 (d; C-3′), 73.1 (d; C-3), 99.9 (d; C-1′), 102.4 (d; C-1), 112.6 (d; ArC-3), 121.9 (d; ArC-5), 122.2 (d; ArC-8), 125.5 (s; ArC-4a), 125.8 (s; ArC-6), 127.1 (d; ArC-7), 128.2 (s; ArC-8a), 129.0 (s; ArC-2), 144.8 (s; ArC-1), 150.0 (s; ArC-4), 169.6 (s; OAc-2), 169.8 (s; OAc-2′), 169.8 (s; OAc-4), 169.8 (s; OAc-4), 170.3 (s; OAc-3′), 170.4 (s; OAc-3), 170.5 (s; OAc-6), 170.7 ppm (s; OAc-6′). IR (Film): v = 2968 (m), 2899 (w), 1742 (s), 1367 (m), 1220 (s), 1170 (m), 1123 (m), 1038 cm−1 (s). HRMS (ESI-Q-TOF): m/z Calcd for C39H46NaO20 [M + Na+]: 857.2475; Found: 857.2477. Anal. Calcd for C39H46O20 (834.78): C 56.11, H 5.55; Found: C 56.03, H 5.61.
2-Ethyl-1,4-bis-(1-O-2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)-naphthalene1d. Obtained as a colorless solid (3.155 g, 74%). m.p. = 218–219 °C. Rf = 0.22 (PE/EtOAc 1:1). [α ] D 23 = −28 (c 1.01, CHCl3). 1H-NMR (600 MHz, CD2Cl2): δ = 1.25 (t, J = 7.6 Hz, 3H; CH3), 1.89 (s, 3H; 6-OAc), 1.99 (s, 3H; 4-OAc), 2.03 (s, 3H; 2′-OAc), 2.03 (s, 3H; 3-OAc), 2.04 (s, 3H; 3′-OAc), 2.05 (s, 3H; 4′-OAc), 2.07 (s, 3H; 6′-OAc), 2.19 (s, 3H; 2-OAc), 2.88 (q, J = 7.6 Hz, 2H; CH2), 3.55 (ddd, J = 10.0, 5.0, 2.6 Hz, 1H; 5-H), 3.94 (dd, J = 12.2, 2.6 Hz, 1H; 6a-H), 4.00 (ddd, J = 10.1, 5.7, 2.5 Hz, 1H, 5′-H), 4.15 (dd, J = 12.2, 5.0 Hz, 1H; 6b-H), 4.22 (dd, J = 12.3, 2.5 Hz, 1H; 6a′-H), 4.26 (dd, J = 12.3, 5.7 Hz, 1H; 6b′-H), 5.04 (d, J = 8.1 Hz, 1H; 1-H), 5.17 (dd, J = 10.0, 9.4 Hz, 1H; 4-H), 5.18 (dd, J = 10.1, 9.3 Hz, 1H; 4′-H), 5.26 (d, J = 7.8 Hz, 1H; 1′-H), 5.29 (dd, J = 9.8, 9.4 Hz, 1H; 3-H), 5.37 (dd, J = 9.8, 9.3 Hz, 1H; 3′-H), 5.44 (dd, J = 9.8, 8.1 Hz, 1H; 2-H), 5.44 (dd, J = 9.8, 7.8 Hz, 1H; 2′-H), 6.98 (s, 1H; 3-ArH), 7.46 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H; 6-ArH), 7.52 (ddd, J = 8.5, 6.8, 1.4 Hz, 1H; 7-ArH), 8.00 (ddd, J = 8.4, 1.4, 0.6 Hz, 1H; 5-ArH), 8.14 ppm (ddd, J = 8.5, 1.3, 0.6 Hz, 1H; 8-ArH). 13C-NMR (150 MHz, CD2Cl2): δ = 15.1 (q; CH3), 20.7 (q; OAc-6), 20.8 (q; OAc-4), 20.8 (q; OAc-2′), 20.8 (2q; OAc-2, OAc-3′), 20.8 (q; OAc-4′), 20.9 (q; OAc-6′), 21.0 (q; OAc-2), 23.5 (t; CH2), 62.0 (t; C-6), 62.6 (t; C-6′), 68.8 (d; C-4), 68.8 (d; C-4′), 71.4 (d; C-2′), 72.2 (C-5), 72.2 (d; C-2), 72.7 (d; C-5′), 72.7 (d; C-3′), 73.2 (d; C-3), 100.0 (d; C-1′), 102.4 (d; C-1), 110.9 (d; ArC-3), 121.9 (d; ArC-5), 122.5 (d; ArC-8), 125.6 (s; ArC-4a), 125.9 (s; ArC-6), 127.1 (d; ArC-7), 129.0 (s; ArC-8a), 134.2 (s; ArC-2), 144.0 (s; ArC-1), 150.4 (s; ArC-4), 169.6 (s; OAc-2′), 169.8 (s; OAc-2), 169.8 (s; OAc-4′), 169.8 (s; OAc-4), 170.3 (s; OAc-3′), 170.4 (s; OAc-3), 170.6 (s; OAc-6), 170.8 ppm (s; OAc-6′). IR (Film): v = 3667 (w), 3482 (w), 2970 (m), 2901 (m), 1746 (s), 1365 (m), 1211 (s), 1170 (m), 1034 cm−1 (s). HRMS (ESI-Q-TOF): m/z Calcd for C40H48NaO20 [M + Na+]: 871.2631; Found: 871.2634. Anal. Calcd for C40H48O20 (848.80): C 56.60, H 5.70; Found: C 56.85, H 5.83.
2-iPropyl-1,4-bis-(1-O-2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)-naphthalene1e. Obtained as a colorless solid (3.375 g, 74%). m.p. = 219–220 °C. Rf = 0.27 (PE/EtOAc 1:1). [α ] D 23 = −26 (c 1.01, CHCl3). 1H-NMR (600 MHz, CD2Cl2): δ = 1.23 (d, J = 6.9 Hz, 3H; CH3), 1.24 (d, J = 6.9 Hz, 3H; CH3), 1.91 (s, 3H; 6-OAc), 1.99 (s, 3H; 4-OAc), 2.03 (s, 3H; 3-OAc), 2.04 (2s, 6H; 2′-OAc, 3′-OAc), 2.05 (s, 3H; 4′-OAc), 2.06 (s, 3H; 6′-OAc), 2.20 (s, 3H; 2-OAc), 3.55 (ddd, J = 10.0, 4.8, 2.5 Hz, 1H; 5-H), 2.88 (sept; J = 6.9 Hz, 1H; CH), 3.95 (dd, J = 12.3, 2.5 Hz, 1H; 6a-H), 4.01 (ddd, J = 10.1, 5.2, 2.8 Hz, 1H, 5′-H), 4.13 (dd, J = 12.3, 4.8 Hz, 1H; 6b-H), 4.22 (dd, J = 12.4, 2.8 Hz, 1H; 6a′-H), 4.25 (dd, J = 12.4, 5.2 Hz, 1H; 6b′-H), 5.05 (d, J = 8.0 Hz, 1H; 1-H), 5.17 (dd, J = 10.0, 9.4 Hz, 1H; 4-H), 5.18 (dd, J = 10.1, 9.3 Hz, 1H; 4′-H), 5.27 (d, J = 7.8 Hz, 1H; 1′-H), 5.30 (dd, J = 9.8, 9.4 Hz, 1H; 3-H), 5.38 (dd, J = 9.7, 9.3 Hz, 1H; 3′-H), 5.44 (dd, J = 9.7, 7.8 Hz, 1H; 2′-H), 5.44 (dd, J = 9.8, 8.0 Hz, 1H; 2-H), 7.02 (s, 1H; 3-ArH), 7.47 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H; 6-ArH), 7.53 (ddd, J = 8.5, 6.8, 1.3 Hz, 1H; 7-ArH), 8.01 (ddd, J = 8.4, 1.3, 0.7 Hz, 1H; 5-ArH), 8.14 ppm (ddd, J = 8.5, 1.2, 0.7 Hz, 1H; 8-ArH). 13C-NMR (150 MHz, CD2Cl2): δ = 20.7 (q; OAc-6), 20.8 (q; OAc-4), 20.8 (q; OAc-2), 20.8 (2q; OAc-2′, OAc-3′), 20.9 (q; OAc-4′), 21.0 (q; OAc-6′), 21.0 (q; OAc-2), 23.4 (q; CH3), 23.9 (q; CH3), 26.6 (d; CH), 62.1 (t; C-6), 62.7 (t; C-6′), 68.7 (d; C-4), 68.7 (d; C-4′), 71.3 (d; C-2′), 72.2 (C-5), 72.2 (d; C-2), 72.7 (d; C-3′), 72.7 (d; C-5′), 73.2 (d; C-3), 100.0 (d; C-1′), 102.3 (d; C-1), 108.0 (d; ArC-3), 121.9 (d; ArC-5), 122.4 (d; ArC-8), 125.6 (s; ArC-4a), 125.9 (s; ArC-6), 127.1 (d; ArC-7), 128.8 (s; ArC-8a), 138.9 (s; ArC-2), 142.8 (s; ArC-1), 150.7 (s; ArC-4), 169.6 (s; OAc-2′), 169.7 (s; OAc-2), 169.8 (s; OAc-4), 169.8 (s; OAc-4′), 170.3 (s; OAc-3′), 170.5 (s; OAc-3), 170.6 (s; OAc-6), 170.8 ppm (s; OAc-6′). IR (Film): v = 3667 (w), 3482 (w), 2969 (m), 2897 (w), 1746 (s), 1601 (w), 1365 (m), 1212 (s), 1171 (m), 1035 cm−1 (s). HRMS (ESI-Q-TOF): m/z Calcd for C41H50NaO20 [M + Na+]: 871.2631; Found: 871.2634. Anal. Calcd for C41H50O20 (862.83): C 57.07, H 5.84; Found: C 56.98, H 5.90.
2-tButyl-1,4-bis-(1-O-2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)-naphthalene1f. Obtained as a colorless solid (3.106 g, 71%). m.p. = 230–231 °C. Rf = 0.31 (PE/EtOAc 1:1). [α ] D 24 = −28 (c 1.01, CHCl3). 1H-NMR (600 MHz, CD2Cl2): δ = 1.49 (s, 9H; t-Bu), 1.93 (s, 3H; 6-OAc), 1.98 (s, 3H; 4′-OAc), 2.03 (s, 3H; 3′-OAc), 2.04 (s, 3H; 3-OAc), 2.05 (s, 3H; 4-OAc), 2.05 (s, 3H; 2′-OAc), 2.06 (s, 3H; 6′-OAc), 2.22 (s, 3H; 2-OAc), 3.49 (ddd, J = 10.0, 4.2, 2.5 Hz, 1H; 5-H), 3.92 (dd, J = 12.3, 2.5 Hz, 1H; 6a-H), 3.99 (ddd, J = 10.1, 5.2, 2.9 Hz, 1H, 5′-H), 4.08 (dd, J = 12.3, 4.2 Hz, 1H; 6b-H), 4.21 (dd, J = 12.4, 2.9 Hz, 1H; 6a′-H), 4.24 (dd, J = 12.4, 5.2 Hz, 1H; 6b′-H), 5.17 (dd, J = 10.1, 9.4 Hz, 1H; 4-H), 5.18 (dd, J = 10.0, 9.3 Hz, 1H; 4′-H), 5.24 (d, J = 7.8 Hz, 1H; 1′-H), 5.25 (d, J = 8.1 Hz, 1H; 1-H), 5.30 (dd, J = 9.8, 9.4 Hz, 1H; 3-H), 5.37 (dd, J = 9.8, 9.3 Hz, 1H; 3′-H), 5.43 (dd, J = 9.8, 7.8 Hz, 1H; 2′-H), 5.45 (dd, J = 9.7, 8.1 Hz, 1H; 2-H), 7.19 (s, 1H; 3-ArH), 7.47 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H; 6-ArH), 7.54 (ddd, J = 8.5, 6.8, 1.3 Hz, 1H; 7-ArH), 7.99 (ddd, J = 8.3, 1.3, 0.6 Hz, 1H; 5-ArH), 8.06 ppm (ddd, J = 8.5, 1.2, 0.6 Hz, 1H; 8-ArH). 13C-NMR (150 MHz, CD2Cl2): δ = 20.7 (q; OAc-6), 20.8 (q; OAc-4′), 20.8 (q; OAc-3), 20.8 (2q; OAc-2′, OAc-3′), 20.9 (q; OAc-4), 21.0 (q; OAc-6′), 21.1 (q; OAc-2), 32.3 (q; t-Bu), 36.8 (s; t-Bu), 61.7 (t; C-6), 62.8 (t; C-6′), 68.6 (d; C-4), 68.7 (d; C-4′), 71.3 (d; C-2′), 72.0 (C-5), 72.3 (d; C-2), 72.7 (d; C-3′), 72.8 (d; C-5′), 73.1 (d; C-3), 100.2 (d; C-1′), 100.8 (d; C-1), 111.1 (d; ArC-3), 122.0 (d; ArC-5), 122.5 (d; ArC-8), 125.9 (d; ArC-6), 126.0 (s; ArC-4a), 126.9 (d; ArC-7), 128.4 (s; ArC-8a), 139.9 (s; ArC-2), 143.2 (s; ArC-1), 149.5 (s; ArC-4), 169.6 (s; OAc-2), 169.7 (s; OAc-2′), 169.8 (s; OAc-4), 169.9 (s; OAc-4′), 170.3 (s; OAc-3), 170.4 (s; OAc-3′), 170.6 (s; OAc-6), 170.8 ppm (s; OAc-6′). IR (Film): v = 2965 (w), 1741 (s), 1434 (w), 1369 (m), 1220 (s), 1034 cm−1 (s). HRMS (ESI-Q-TOF): m/z Calcd for C42H52NaO20 [M + Na+]: 899.2944; Found: 899.2949. Anal. Calcd for (%) C42H52O20 (876.86): C 57.53, H 5.98; Found: C 57.37, H 6.06.

3.4. Photooxygenation of Carbohydrate-Substituted Naphthalenes 1 to Endoperoxides 2

A solution of naphthalene 1 (0.15 mmol) and sensitizer tetraphenylporphyrin (TPP, 1.0 mg) in CD2Cl2 (3.0 mL) was cooled to −70 °C, oxygen was slowly bubbled through the solution, and the mixture was irradiated externally with a sodium lamp (400 W) for 2 h. NMR spectra (500 MHz), which were directly measured from the crude products at −70 °C, showed complete conversion and the sole formation of endoperoxides 2. The diastereomeric ratios (dr) could be easily determined by integration of the distinctive signals of H3, which are separated by 0.2 ppm (for NMR spectra, see Supplementary Materials; the characteristic chemical shifts of the minor isomers are marked bold). The reaction of tBu derivative 1f with 1O2 was conducted on a preparative scale as well. Thus, naphthalene 1f (877 mg, 1.0 mmol) and TPP (15 mg) were dissolved in dichloromethane (100 mL) and the solution was photooxygenated at −70 °C for 2 h, as described above. The solvent was removed in vacuo and direct column chromatography (hexanes/EtOAc 1:1) at room temperature afforded endoperoxide 1S,4R-2f (417 mg, 46%) and 1R,4S-2f (373 mg, 41%) in pure form.
Endoperoxide2b.Rf = 0.56 (PE/EtOAc 3:1). 1H-NMR (500 MHz, CD2Cl2, −78 °C): δ = 1.93 (s, 3H; OAc), 1.99 (s, 3H; OAc), 1.99 (s, 3H; OAc), 2.00 (s, 6H; OAc), 2.00 (s, 3H; OAc), 2.05 (s, 3H; OAc), 2.06 (s, 3H; OAc), 3.84 (ddd, J = 9.9, 4.7, 2.1 Hz, 1H; 5-H), 3.88 (ddd, J = 10.0, 3.8, 2.4 Hz, 1H; 5′-H), 4.01 (dd, J = 12.5, 2.4 Hz, 1H; 6a’-H), 4.06 (dd, J = 12.5, 2.1 Hz, 1H; 6a-H), 4.28 (m, 2H; 6b-H, 6b’-H), 5.13 (dd, J = 10.0, 9.7 Hz, 1H; 4′-H), 5.16 (dd, J = 9.9, 9.5 Hz, 1H; 4-H), 5.19–5.31 (m, 6H; 1-H, 1′-H, 2-H, 2′-H, 3-H, 3′-H); 6.94 (d, J = 9.3 Hz, 1H; 3-ArH), 7.16 (d, J = 9.3 Hz, 1H; 2-ArH), 7.28–7.33 (m, 2H; 6-ArH, 7-ArH), 7.35–7.39 (m, 1H; 8-ArH), 7.43–7.46 ppm (m, 1H; 5-ArH). 13C-NMR (125 MHz, CD2Cl2, –78 °C): δ = 20.6 (q; 2 x OAc), 20.6 (q; 3 x OAc), 20.7 (q; 2 x OAc), 20.7 (q; OAc), 61.0 (t; C-6), 61.1 (t; C-6′), 66.5 (d; C-4), 66.8 (d; C-4′), 69.4 (d; C-2′), 70.1 (d; C-2), 70.9 (d; C-3′), 71.2 (d; C-3), 71.5 (d; C-5′), 71.6 (d; C-5), 96.5 (d; C-1′), 96.6 (d; C-1), 101.7 (s; ArC-1), 102.8 (s; ArC-4), 119.2 (d; ArC-8), 119.4 (d; ArC-5), 127.5 (d; ArC-6), 127.6 (d; ArC-7), 133.3 (s; ArC-4a), 135.5 (d; ArC-2), 135.9 (s; ArC-8a), 136.0 (d; ArC-3), 169.1 (s; OAc), 169.4 (s; OAc), 169.4 (s; OAc), 169.5 (s; OAc), 170.0 (s; OAc), 170.2 (s; OAc), 170.6 (s; OAc-6), 170.6 ppm (s; OAc-6‘). HRMS (ESI-Q-TOF): m/z Calcd for C38H45O22 [M + H+]: 853.2402; Found: 853.2427.
Endoperoxide2c.Rf = 0.51 (PE/EtOAc 3:1). 1H-NMR (500 MHz, CD2Cl2, −78 °C): δ = 1.81 (d, J = 1.4 Hz, 3H; Me), 1.94 (s, 3H; OAc), 1.98 (s, 3H; OAc), 1.99 (s, 3H; OAc), 2.00 (s, 3H; OAc), 2.00 (s, 3H; OAc), 2.04 (s, 3H; 6′-OAc), 2.06 (s, 3H; OAc), 2.15 (s, 3H; 6-OAc), 3.82 (ddd, J = 9.7, 5.4, 2.1 Hz, 1H; 5-H), 3.89 (ddd, J = 9.8, 5.4, 2.3 Hz, 1H; 5′-H), 4.07 (dd, J = 12.5, 2.3 Hz, 1H; 6a’-H), 4.13 (dd, J = 12.3, 2.1 Hz, 1H; 6a-H), 4.19−4.25 (m, 2H; 6b-H, 6b’-H), 5.05 (dd, J = 9.8, 9.7 Hz, 1H; 4′-H), 5.15 (dd, J = 9.8, 9.7 Hz, 1H; 4-H), 5.13–5.33 (m, 6H; 2-H, 1-H, 2′-H, 1′-H, 3-H, 3′-H), 6.43 (d, J = 1.5 Hz, 1H; 3-ArH), 6.61 (d, J = 1.4 Hz, 1H; 3-ArH), 7.26 (ddd, J = 7.4, 7.3, 1.2 Hz, 1H; 7-ArH), 7.31 (ddd, J = 7.4, 7.4, 1.2 Hz, 1H; 6-ArH), 7.34 (dd, J = 7.4, 1.3 Hz, 1H; 5-ArH, 6-ArH, 7-ArH), 7.39–7.40 (m, 1H; 5-ArH), 7.53–7.55 (m, 1H; 8-ArH), 7.85 ppm (dd, J = 7.3, 1.2 Hz, 1H; 8-ArH). 13C-NMR (125 MHz, CD2Cl2, −78 °C)a: δ = 14.7 (q; Me), 20.6 (q; 2 x OAc), 20.6 (q; 3 x OAc), 20.7 (q; OAc), 20.8 (q; OAc), 21.0 (q; OAc), 61.4 (t; C-6′), 62.1 (t; C-6), 67.0 (d; C-4), 67.4 (d; C-4′), 69.5 (d; C-2′), 69.8 (d; C-2), 70.7 (d; C-3), 70.9 (d; C-3′), 71.5 (d; C-5′), 71.7 (d; C-5), 96.1 (2d; C-1, C-1‘), 101.7 (s; ArC-4), 104.0 (s; ArC-1), 118.6 (d; ArC-5), 120.3 (d; ArC-8), 125.2 (d; ArC-3), 126.9 (d; ArC-7), 127.7 (d; ArC-6), 134.0 (s; ArC-8a), 138.8 (s; ArC-4a), 149.1 (d; ArC-2), 169.3 (s; OAc), 169.5 (s; OAc), 169.6 (s; OAc), 169.7 (s; OAc), 169.9 (s; OAc), 170.0 (s; OAc), 170.5 (s; OAc-6‘), 170.6 ppm (s; OAc-6).
Endoperoxide2d.Rf = 0.44 (PE/EtOAc 2:1). 1H-NMR (500 MHz, CD2Cl2, −20 °C): δ = 0.97 (d, J = 7.2 Hz, 3H; CH3), 1.97 (s, 3H; OAc), 1.99 (s, 3H; OAc), 2.00 (2s, 6H; 2 x OAc), 2.02 (s, 3H; OAc), 2.03 (s, 3H; OAc), 2.06 (s, 3H; 6′-OAc), 2.14 (s, 3H; 6-OAc), 2.73 (dq; J = 7.2, 1.7 Hz, 2H; CH2), 3.82 (ddd, J = 10.0, 6.0, 2.2 Hz, 1H; 5-H), 3.91 (ddd, J = 10.0, 6.5, 2.1 Hz, 1H; 5′-H), 4.12 (dd, J = 12.2, 2.1 Hz, 1H; 6a’-H), 4.19 (dd, J = 12.5, 6.0 Hz, 1H; 6b-H), 4.20 (dd, J = 12.5, 2.2 Hz, 1H; 6a-H), 4.27 (dd, J = 12.2, 6.5 Hz, 1H; 6‘b-H), 5.06−5.11 (m, 2H; 4-H, 4′-H), 5.16 (dd, J = 9.8, 7.8 Hz, 1H; 2-H), 5.17–5.26 (m, 4H; 2′-H, 3′-H, 1-H, 1′-H); 5.31 (dd, J = 9.6, 9.0 Hz, 1H; 3′-H), 6.31 (s, 1H; 3-ArH), 6.54 (t, J = 1.7 Hz, 1H; 3-ArH), 7.26 (ddd, J = 7.6, 7.5, 1.0 Hz, 1H; 7-ArH), 7.32 (ddd, J = 7.5, 7.4, 0.9 Hz, 1H; 6-ArH, 6-ArH, 7-ArH), 7.38 (dd, J = 7.4, 1.0 Hz, 1H; 5-ArH), 7.45–7.47 (m, 1H; 5-ArH), 7.55–7.57 (m, 1H; 8-ArH), 7.88 ppm (dd, J = 7.6, 0.9 Hz, 1H; 8-ArH). 13C-NMR (125 MHz, CD2Cl2, –20 °C): δ = 10.2 (q; CH3), 20.7 (q; OAc), 20.7 (q; OAc), 20.7 (q; 2 x OAc), 20.7 (q; OAc), 20.8 (q; OAc), 20.9 (q; OAc), 21.0 (q; CH3), 21.1 (q; OAc), 62.3 (t; C-6′), 62.5 (t; C-6), 67.9 (d; C-4‘), 68.1 (d; C-4), 70.2 (d; C-2′), 70.6 (d; C-2), 71.7 (d; C-3‘), 71.8 (d; C-3), 72.3 (d; C-5′), 72.4 (d; C-5), 96.5 (d; C-1), 96.7 (d; C-1‘), 102.5 (s; ArC-4), 104.6 (s; ArC-1), 119.0 (d; ArC-5), 120.7 (d; ArC-8), 123.5 (d; ArC-3), 127.2 (d; ArC-7), 127.9 (d; ArC-6), 135.2 (s; ArC-8a), 139.6 (s; ArC-4a), 155.1 (d; ArC-2), 169.5 (s; OAc), 169.7 (s; OAc), 169.7 (s; OAc), 169.8 (s; OAc), 170.0 (s; OAc), 170.1 (s; OAc), 170.6 (s; OAc-6), 170.7 ppm (s; OAc-6‘).
Endoperoxide2e.Rf = 0.47 (PE/EtOAc 2:1). 1H-NMR (500 MHz, CD2Cl2, −20 °C): δ = 0.90 (d, J = 6.7 Hz, 3H; CH3), 1.04 (d, J = 6.8 Hz, 3H; CH3), 1.97 (s, 3H; OAc), 1.99 (s, 3H; OAc), 2.00 (s, 3H; OAc), 2.00 (s, 3H; OAc), 2.02 (s, 3H; OAc), 2.03 (s, 3H; 6′-OAc), 2.05 (s, 3H; 2-OAc), 2.14 (s, 3H; 6-OAc), 2.73 (dsept; J = 6.8, 1.4 Hz, 1H; CH), 3.83 (ddd, J = 10.1, 6.5, 2.4 Hz, 1H; 5-H), 3.91 (ddd, J = 10.0, 6.0, 2.1 Hz, 1H; 5′-H), 4.12 (dd, J = 12.3, 2.1 Hz, 1H; 6a’-H), 4.17 (dd, J = 12.5, 6.0 Hz, 1H; 6b-H), 4.19 (dd, J = 12.5, 2.4 Hz, 1H; 6a-H), 4.24 (dd, J = 12.3, 6.5 Hz, 1H; 6‘b-H), 5.08 (dd, J = 10.0, 9.6 Hz, 1H; 4′-H), 5.10 (dd, J = 10.1, 9.2 Hz, 1H; 4-H), 5.17 (dd, J = 9.5, 7.6 Hz, 1H; 2-H), 5.21 (dd, J = 9.7, 7.8 Hz, 1H; 2′-H), 5.22–5.27 (m, 3H; 3-H, 1-H, 1′-H); 5.31 (dd, J = 9.7, 9.6 Hz, 1H; 3′-H), 6.25 (d, J = 1.6 Hz, 1H; 3-ArH), 6.50 (d, J = 1.4 Hz, 1H; 3-ArH), 7.25 (ddd, J = 7.6, 7.5, 1.2 Hz, 1H; 7-ArH), 7.31 (ddd, J = 7.5, 7.5, 0.9 Hz, 1H; 6-ArH, 6-ArH, 7-ArH), 7.38 (dd, J = 7.4, 1.2 Hz, 1H; 5-ArH), 7.45–7.47 (m, 1H; 5-ArH), 7.59–7.61 (m, 1H; 8-ArH), 7.89 ppm (dd, J = 7.4, 1.0 Hz, 1H; 8-ArH). 13C-NMR (125 MHz, CD2Cl2, –20 °C): δ = 20.1 (q; CH3), 20.7 (q; 2 x OAc), 20.7 (q; 2 x OAc), 20.7 (q; OAc), 20.8 (q; OAc), 20.8 (q; CH3), 20.9 (q; OAc), 21.0 (q; OAc), 27.0 (d; CH), 62.4 (t; C-6′), 62.6 (t; C-6), 67.9 (d; C-4‘), 68.1 (d; C-4), 70.2 (d; C-2′), 70.7 (d; C-2), 71.8 (d; C-3‘), 71.9 (d; C-3), 72.3 (d; C-5′), 72.4 (d; C-5), 96.5 (d; C-1), 96.7 (d; C-1‘), 102.4 (s; ArC-4), 104.9 (s; ArC-1), 119.1 (d; ArC-5), 120.5 (d; ArC-8), 122.4 (d; ArC-3), 127.2 (d; ArC-7), 127.9 (d; ArC-6), 135.7 (s; ArC-8a), 139.6 (s; ArC-4a), 159.3 (d; ArC-2), 169.5 (s; OAc), 169.7 (s; OAc), 169.7 (s; OAc), 169.7 (s; OAc), 170.0 (s; OAc), 170.1 (s; OAc), 170.7 (s; OAc-6), 170.7 ppm (s; OAc-6‘).
Endoperoxide 1S,4R-2f. Rf = 0.19 (PE/EtOAc 1:1). [α ] D 24 = +13 (c 1.04, CHCl3). 1H-NMR (600 MHz, CD2Cl2): δ = 1.15 (s, 9H; tBu), 1.98 (s, 3H; 3′-OAc), 1.99 (s, 3H; 2-OAc), 2.01 (s, 3H; 3-OAc), 2.02 (2s, 6H; 6′-OAc, 4′-OAc), 2.03 (s, 3H; 4-OAc), 2.06 (s, 3H; 2′-OAc), 2.14 (s, 3H; 6-OAc), 3.81 (ddd, J = 10.0, 5.1, 3.8 Hz, 1H; 5-H), 3.93 (ddd, J = 10.1, 4.5, 3.9 Hz, 1H; 5′-H), 4.15–4.18 (m, 2H; 6a′-H, 6b′-H), 4.21–4.28 (m, 2H; 6a-H, 6b-H), 5.09 (dd, J = 10.1, 9.4 Hz, 1H; 4′-H), 5.13 (dd, J = 10.0, 9.3 Hz, 4-H), 5.19–5.22 (m, 3H; 2′-H, 2-H, 3′-H), 5.28 (d, J = 7.6 Hz, 1H; 1-H), 5.30 (d, J = 7.8 Hz, 1H; 1′-H), 5.32 (dd, J = 9.7, 9.3 Hz, 1H; 3-H), 6.57 (s, 1H; 3-ArH), 7.25 (ddd, J = 7.6, 7.5, 1.3 Hz, 1H; 7-ArH), 7.31 (ddd, J = 7.6, 7.5, 1.1 Hz, 1H; 6-ArH), 7.41 (ddd, J = 7.5, 1.3, 0.5 Hz, 1H; 5-ArH). 7.94 ppm (ddd, J = 7.5, 1.1, 0.5 Hz, 1H; 8-ArH). 13C-NMR (150 MHz, CD2Cl2): δ = 20.8 (q; OAc-3′), 20.8 (q; OAc-2), 20.8 (q; OAc-3), 20.8 (q; OAc-6′), 20.9 (q; OAc-4′), 20.9 (q; OAc-4), 21.0 (q; OAc-2′), 21.0 (q; OAc-6), 28.4 (q; tBu), 35.4 (s; tBu), 62.8 (t; C-6′), 63.0 (t; C-6), 68.7 (d; C-4′), 68.7 (d; C-4), 70.9 (d; C-2), 71.4 (d; C-2′), 72.4 (d; C-3), 72.9 (d; C-5′), 72.9 (d; C-3′), 72.9 (d; C-5), 97.1 (d; C-1′), 97.3 (d; C-1), 102.4 (s; ArC-4), 107.3 (s; ArC-1), 119.6 (d; ArC-5), 120.8 (d; ArC-8), 124.5 (d; ArC-3), 127.3 (d; ArC-7), 128.0 (d; ArC-6), 137.0 (s; ArC-8a), 140.2 (s; ArC-4a), 161.3 (s; ArC-2), 169.7 (2s; OAc-2, OAc-2′), 169.8 (s; OAc-4), 169.9 (s; OAc-4′), 170.1 (s; OAc-3′), 170.2 (s; OAc-3), 170.7 (s; OAc-6), 170.8 ppm (s; OAc-6′). IR (Film): v = 3387 (br), 2927 (w), 1579 (w), 1395 (m), 1266 (w), 1239 (w), 1147 (m), 1072 (s), 1036 cm−1 (s). HRMS (ESI-Q-TOF): m/z Calcd for C42H52NaO22 (M + Na+): 931.2842; Found: 931.2842.
Endoperoxide 1R,4S-2f. Rf = 0.12 (PE/EtOAc 1:1). [α ] D 24 = −2.5 (c 1.01, CHCl3). 1H-NMR (600 MHz, CD2Cl2): δ = 1.15 (s, 9H; tBu), 1.98 (s, 3H; 4-OAc), 1.99 (s, 3H; 2′-OAc), 2.00 (s, 3H; 3-OAc), 2.00 (s, 3H; 3′-OAc), 2.01 (s, 3H; 4′-OAc), 2.03 (s, 3H; 6-OAc), 2.05 (s, 3H; 6′-OAc), 2.14 (s, 3H; 2-OAc), 3.70 (ddd, J = 10.1, 4.8, 2.5 Hz, 1H; 5-H), 3.86 (ddd, J = 10.0, 4.5, 2.4 Hz, 1H; 5′-H), 4.06 (dd, J = 12.3, 2.5 Hz, 1H; 6a-H), 4.08 (dd, J = 12.4, 2.4 Hz, 1H; 6a′-H), 4.23 (dd, J = 12.3, 4.8 Hz, 1H; 6b-H), 4.30 (dd, J = 12.4, 2.4 Hz, 6b’-H), 5.13 (dd, J = 10.1, 9.2 Hz, 1H; 4-H), 5.15 (dd, J = 10.0, 9.5 Hz, 1H; 4′-H), 5.23 (dd, J = 9.7, 8.0 Hz, 1H; 2′-H), 5.28 (dd, J = 9.6, 9.2 Hz, 1H; 3-H), 5.29 (d, J = 8.0 Hz, 1H: 1′-H), 5.31 (dd, J = 9.7, 9.5 Hz, 1H; 3′-H), 5.37 (d, J = 8.1 Hz, 1H; 1-H), 5.37 (dd, J = 9.6, 8.1 Hz, 1H; 2-H), 6.28 (s, 1H; 3-ArH), 7.30–7.33 (m, 2H; 6-ArH, 7-ArH), 7.47–7.49 (m, 1H; 5-ArH), 7.64–7.67 ppm (m, 1H; 8-ArH). 13C-NMR (150 MHz, CD2Cl2): δ = 20.7 (q; OAc-4), 20.7 (3q; OAc-2′, OAc-3, OAc-4′), 20.8 (q; OAc-3′), 20.8 (q; OAc-6), 20.8 (q; OAc-6′), 20.9 (q; OAc-2), 28.2 (q; tBu), 35.5 (s; tBu), 61.9 (t; C-6), 62.0 (t; C-6′), 68.2 (d; C-4′), 68.6 (d; C-4), 71.6 (d; C-2′), 71.8 (d; C-2), 72.5 (d; C-5), 72.8 (2d; C-5′, C-3′), 73.2 (d; C-3), 97.1 (d; C-1), 97.2 (d; C-1′), 103.2 (s; ArC-4), 107.3 (s; ArC-1), 119.9 (d; ArC-5), 120.1 (d; ArC-8), 124.6 (d; ArC-3), 127.3 (d; ArC-7), 128.0 (d; ArC-6), 136.7 (s; ArC-8a), 140.2 (s; ArC-4a), 161.5 (s; ArC-2), 169.1 (s; OAc-2), 169.2 (s; OAc-2′), 169.7 (s; OAc-4′), 169.7 (s; OAc-4), 170.3 (s; OAc-3), 170.3 (s; OAc-3′), 170.7 (s; OAc-6), 170.7 ppm (s; OAc-6′). IR (Film): v = 3387 (br), 2927 (w), 1579 (w), 1395 (m), 1266 (w), 1239 (w), 1147 (m), 1072 (s), 1036 cm−1 (s). HRMS (ESI-Q-TOF): m/z Calcd for C42H52NaO22 (M + Na+): 931.2842; Found: 931.2852.

3.5. Thermolysis of Endoperoxides 2 and Determination of Singlet Oxygen Yield

The half lifetimes of endoperoxides 2 were determined by measuring UV/VIS spectra at different temperatures and observing the increasing absorption band of the corresponding naphthalene 1 at 290–320 nm. The singlet oxygen yield was determined by trapping with tetramethylethylene. Thus, the cold solution of crude endoperoxide 2b was purged with argon for 2 min, 20 equiv. of tetramethylethylene were added, and the solution was warmed to room temperature within 8 h. The 1O2 yield was then determined by 1H-NMR integrals of the formed hydroperoxide.

3.6. Transformation of Endoperoxide 1S,4R-2f into Enantiomerically Pure Epoxide 2S,3R-8

Endoperoxide 1S,4R-2f (360 mg, 0.4 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 °C, and a cold solution of m-chloroperoxybenzoic acid (70 mg, 0.4 mmol) in dichloromethane (10 mL) was added at 0 °C. After 16 h at 0 °C, TLC showed incomplete conversion and another amount of m-chloroperoxybenzoic acid (35 mg, 0.2 mmol) in dichloromethane (5 mL) was added. After 2 days at room temperature, the reaction mixture was extracted with a saturated solution of potassium carbonate (2 × 20 mL), washed with water (20 mL), and dried over sodium sulfate. After removal of solvent in vacuo, the crude product was purified by column chromatography (hexanes/EtOAc 1:1) to afford epoxide syn-7 (280 mg, 76%) as sole diastereomer.
Rf = 0.16 (PE/EtOAc 1:1). [α ] D 24 = +66 (c 0.99, CHCl3). 1H-NMR (400 MHz, CDCl3): δ = 0.92 (s, 9H; tBu), 1.99 (s, 3H; OAc), 2.02 (s, 3H; OAc), 2.03 (s, 3H; OAc), 2.03 (s, 3H; OAc), 2.04 (s, 3H; OAc), 2.06 (s, 3H; OAc), 2.15 (s, 3H; OAc), 2.18 (s, 3H; OAc), 3.77–3.82 (m, 1H; 5-H), 3.92 (s, 1H; 3-H), 3.93–4.00 (m, 1H; 5′-H), 4.19–4.28 (m, 4H; 6a′-H, 6b′-H, 6a-H, 6b-H), 5.09–5.26 (m, 6H; 1′-H, 2-H, 2′-H, 3′-H, 4-H, 4′-H), 5.32–5.38 (m, 2H; 3-H, 1-H), 7.42–7.57 (m, 3-ArH; 5-ArH, 6-H, 7-ArH), 8.03–8.06 ppm (m, 8-ArH). 13C-NMR (100 MHz, CDCl3): δ = 20.8 (2q; OAc), 20.8 (3q; OAc), 20.8 (q; OAc), 21.0 (q; OAc), 21.0 (q; OAc), 26.5 (q; tBu), 32.9 (s; tBu), 61.0 (d; C-3), 62.5 (t; C-6′), 62.8 (t; C-6), 68.6 (d; C-4′), 68.9 (d; C-4), 70.9 (d; C-2), 71.3 (d; C-2′), 71.4 (s; ArC-2), 72.4 (d; C-3), 72.6 (d; C-5′), 73.0 (d; C-3′), 73.1 (d; C-5), 97.1 (d; C-1′), 97.1 (d; C-1), 100.1 (s; ArC-4), 106.4 (s; ArC-1), 121.3 (d; ArC-5), 123.5 (d; ArC-8), 129.1 (d; ArC-7), 129.3 (d; ArC-6), 137.0 (d; ArC-8a), 138.4 (s; ArC-4a),169.6 (s; OAc), 169.9 (3s; OAc), 170.1 (s; OAc), 170.2 (s; OAc), 170.7 (s; OAc), 170.7 ppm (s; OAc-6′). IR (Film): ν = 3660 (w), 3501 (w), 1743 (s), 1434 (m), 1364 (s), 1214 (s), 1037 (s). HRMS (ESI-Q-TOF): m/z Calcd for C42H52NaO23 (M + Na+): 947.2792, Found: 947.2790.
Epoxide syn-7 (190 mg, 0.2 mmol) was dissolved in dichloromethane (10 mL), and palladium on charcoal (20 mg, 5 mol%) was added. The solution was purged with hydrogen gas for 5 min, equipped with a balloon filled with hydrogen gas and hydrogenated under stirring at 1 bar for 16 h. The solvent was removed in vacuo, and column chromatography (hexanes/EtOAc 1:1) afforded epoxide 8 (30 mg, 63%) as a white solid in enantiomerically pure form, which was confirmed by HPLC on a chiral phase (for chromatograms, see Figure 5).
M.p. = 61–63 °C. Rf = 0.81 (PE/EtOAc 1:1). [α ] D 25 = −22 (c 1.00, CHCl3). 1H-NMR (400 MHz, CDCl3): δ = 1.23 (s, 9H; tBu), 3.99 (s, 1H; 3-H), 7.67–7.76 (m, 2H; 5-H, 6-H), 7.88–7.91 (m, 1H; 3-H, 5-H), 7.96–7.99 ppm (m, 1H; 8-H). 13C-NMR (100 MHz, CDCl3): δ = 26.3 (q; t-Bu), 33.0 (s; t-Bu), 58.8 (d; C-3), 68.4 (s; C-2), 126.3 (d; C-5), 127.8 (d; C-8), 131.3 (s; C-4a), 134.0 (d; C-6), 134.2 (s; C-8a), 134.7 (d; C-7), 191.5 (s; C-1), 192.7 ppm (s; C-4). IR (Film): ν = 3484(w, br), 2962 (w), 2921 (w), 2877 (w), 1695 (s), 1596 (s), 1461 (m), 1341 (m), 1322 (m), 1299 (s), 1143 (s), 916 (s), 881 (s). LRMS (GC-TOF): m/z Calcd for C14H14O3 (M+): 230.0943; Found: 230.0941.

4. Conclusions

In conclusion, we could control the [4+2] cycloaddition of singlet oxygen to naphthalenes by carbohydrates. Such a chiral auxiliary approach with sugars was hitherto unknown. The precursors are easily available from naphthoquinone and Schmidt’s trichloroacetimidate in only 2–3 steps. The photooxygenations afforded endoperoxides (EPOs) as sole products, which were characterized by low-temperature NMR, but can reconvert to the parent naphthalenes under release of singlet oxygen. However, sterically demanding EPOs could be isolated by column chromatography in enatiomerically pure form at room temperature for the first time. Their absolute configurations were determined by a combination of NOESY measurements and theoretical calculations. We found a remarkable influence of substituents on the diastereoselectivities of the photooxygenations, ranging from no selectivity to up to 91:9 dr, which was rationalized by preferred rotamers of the carbohydrates. Thus, the sugars control the attack of singlet oxygen by steric and electrostatic repulsions. Finally, we could transfer the chiral information of the EPOs to an epoxide with high selectivity. After removal of the carbohydrates, we obtained a naphthoquinone epoxide in enantiomerically pure form, proven by HPLC on a chiral phase. This allowed the unequivocal determination of the absolute configurations of the EPOs. Furthermore, since the carbohydrates can be easily introduced, influence the selectivities of the photooxygenations, and are finally cleaved, the concept of a chiral auxiliary controlled [4+2] cycloaddition of singlet oxygen to naphthalenes has been realized.

Supplementary Materials

The following are available online, S2–S5: 1H- and 13C-NMR spectra of naphthoquinones 3, S6–S10: 1H- and 13C-NMR spectra of carbohydrate-substituted naphthalenes 1, S11–S17: 1H- and 13C-NMR spectra of endoperoxides 2, S18–S19: NOESY spectra of endoperoxides 2f, S20–S21: 1H- and 13C-NMR spectra of epoxides 7 and 8, S22–S30: theoretical calculations.

Author Contributions

Conceptualization, T.L.; synthesis, M.B.; NMR evaluation, M.B.; calculations, M.B. and W.F.; HPLC analysis, W.F.; writing T.L.; funding acquisition, T.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the University of Potsdam, Germany.

Data Availability Statement

The data presented in this study are available in this article.

Acknowledgments

We thank Melanie Metz for the synthesis of some starting materials.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not available.

References

  1. Nonell, S.; Flors, C. (Eds.) Singlet Oxygen; Comprehensive Series in Photochemical & Photobiological Sciences; The Royal Society of Chemistry: London, UK, 2016; Volume 1, ISBN 978-1-78262-038-9. [Google Scholar]
  2. Gorman, A.A.; Rodgers, M.A.J. Singlet molecular oxygen. Chem. Soc. Rev. 1981, 10, 205–231. [Google Scholar] [CrossRef]
  3. Ogilby, P.R.; Foote, C.S. Chemistry of singlet oxygen. 42. Effect of solvent, solvent isotopic substitution, and temperature on the lifetime of singlet molecular oxygen. J. Am. Chem. Soc. 1983, 105, 3423–3430. [Google Scholar] [CrossRef]
  4. Kuimova, M.K.; Yahioglu, G.; Ogilby, P.R. Singlet Oxygen in a Cell: Spatially Dependent Lifetimes and Quenching Rate Constants. J. Am. Chem. Soc. 2009, 131, 332–340. [Google Scholar] [CrossRef] [Green Version]
  5. Stratakis, M.; Orfanopoulos, M. Regioselectivity in the Ene Reaction of Singlet Oxygen with Alkenes. Tetrahedron 2000, 56, 1595–1615. [Google Scholar] [CrossRef]
  6. Prein, M.; Adam, W. The Schenck Ene Reaction: Diastereoselective Oxyfunctionalization with Singlet Oxygen in Synthetic Applications. Angew. Chem. (Int. Ed. Engl.) 1996, 35, 477–494. [Google Scholar] [CrossRef]
  7. Adam, W.; Nestler, B. Photooxygenation of chiral allylic alcohols: Hydroxy-directed regio- and diastereoselective ene reaction of singlet oxygen. J. Am. Chem. Soc. 1992, 114, 6549–6550. [Google Scholar] [CrossRef]
  8. Adam, W.; Nestler, B. Hydroxy-Directed Regio- and Diastereoselective Ene Reaction of Singlet Oxygen with Chiral Allylic Alcohols. J. Am. Chem. Soc. 1993, 115, 5041–5049. [Google Scholar] [CrossRef]
  9. Adam, W.; Prein, M. Diastereoselective [4+2] cycloaddition of singlet oxygen in the photooxygenation of chiral naphthyl alcohols: Evidence for a hydroxy group-directing effect. J. Am. Chem. Soc. 1993, 115, 3766–3767. [Google Scholar] [CrossRef]
  10. Adam, W.; Prein, M. π-Facial Diastereoselectivity in the [4+2] Cycloaddition of Singlet Oxygen as a Mechanistic Probe. Acc. Chem. Res. 1996, 29, 275–283. [Google Scholar] [CrossRef]
  11. Adam, W.; Prein, M. Substituent effects in the diastereoselective [4+2] cycloaddition of chiral naphthalene derivatives with singlet oxygen. Tetrahedron Lett. 1994, 35, 4331–4334. [Google Scholar] [CrossRef]
  12. Linker, T.; Fröhlich, L. Regio- and Diastereoselective Photooxygenation of Chiral 2,5-Cyclohexadiene-l-carboxylic Acids. Angew. Chem. Int. Ed. Engl. 1994, 33, 1971–1972. [Google Scholar] [CrossRef]
  13. Linker, T.; Fröhlich, L. Substituent Effects in the Highly Regioselective and Diastereoselective Ene Reaction of Singlet Oxygen with Chiral Cyclohexadienes. J. Am. Chem. Soc. 1995, 117, 2694–2697. [Google Scholar] [CrossRef]
  14. Sundén, H.; Engqvist, M.; Casas, J.; Ibrahem, I.; Córdova, A. Direct amino acid catalyzed asymmetric α oxidation of ketones with molecular oxygen. Angew. Chem. Int. Ed. 2004, 43, 6532–6535. [Google Scholar] [CrossRef]
  15. Córdova, A.; Sundén, H.; Engqvist, M.; Ibrahem, I.; Casas, J. The Direct Amino Acid-Catalyzed Asymmetric Incorporation of Molecular Oxygen to Organic Compounds. J. Am. Chem. Soc. 2004, 126, 8914–8915. [Google Scholar] [CrossRef]
  16. Walaszek, D.J.; Jawiczuk, M.; Durka, J.; Drapała, O.; Gryko, D. α-Photooxygenation of chiral aldehydes with singlet oxygen. Beilstein J. Org. Chem. 2019, 15, 2076–2084. [Google Scholar] [CrossRef] [Green Version]
  17. Joy, A.; Robbins, R.J.; Pitchumani, K.; Ramamurthy, V. Asymmetrically modified zeolite as a medium for enantioselective photoreactions: Reactions from spin forbidden excited states. Tetrahedron Lett. 1997, 38, 8825–8828. [Google Scholar] [CrossRef]
  18. Griesbeck, A.G.; Bartoschek, A.; Neudörfl, J.; Miara, C. Stereoselectivity in Ene Reactions with Singlet Oxygen: Matrix Effects in Polymer Supports, Photooxygenation of Organic Salts and Asymmetric Synthesis. Photochem. Photobiol. 2006, 82, 1233–1240. [Google Scholar] [CrossRef]
  19. Griesbeck, A.G.; Miranda, M.A.; Uhlig, J. Sweet chiral porphyrins as singlet oxygen sensitizers for asymmetric Type II photooxygenation. Photochem. Photobiol. Sci. 2011, 10, 1431–1435. [Google Scholar] [CrossRef] [PubMed]
  20. Wiegand, C.; Herdtweck, E.; Bach, T. Enantioselectivity in visible light-induced, singlet oxygen [2+4] cycloaddition reactions (type II photooxygenations) of 2-pyridones. Chem. Commun. 2012, 48, 10195–10197. [Google Scholar] [CrossRef] [PubMed]
  21. Adam, W.; Brünker, H.-G.; Nestler, B. Photooxygenation of 2-alkenyl substituted chiral oxazolines: Stereochemical evidence favouring the cis effect in the regioselective ene reaction of singlet oxygen with α,β-unsaturated carbonyl derivatives. Tetrahedron Lett. 1991, 32, 1957–1960. [Google Scholar] [CrossRef]
  22. Dussault, P.H.; Woller, K.R.; Hillier, M.C. Stereoselective dioxygenation of enoates. Tetrahedron 1994, 50, 8929–8940. [Google Scholar] [CrossRef]
  23. Fudickar, W.; Vorndran, K.; Linker, T. Auxiliary controlled singlet-oxygen ene reactions of cyclohexenes. Tetrahedron 2006, 62, 10639–10646. [Google Scholar] [CrossRef]
  24. Adam, W.; Peters, K.; Peters, E.-M.; Schambony, S.B. Diastereoselective and Regioselective Singlet-Oxygen Ene Reaction of Oxazolidine-Substituted Alkenes:  Control through Hydrogen Bonding Mediated by the Urea Functionality of Chiral Auxiliaries. J. Am. Chem. Soc. 2000, 122, 7610–7611. [Google Scholar] [CrossRef]
  25. Adam, W.; Degen, H.G.; Krebs, O.; Saha-Möller, C.R. Efficient π-facial control in the ene reaction of nitrosoarene, triazolinedione, and singlet oxygen with tiglic amides of the bornane-derived sultam as chiral auxiliary. J. Am. Chem. Soc. 2002, 124, 12938–12939. [Google Scholar] [CrossRef] [PubMed]
  26. Adam, W.; Bosio, S.G.; Turro, N.J. Highly diastereoselective dioxetane formation in the photooxygenation of enecarbamates with an oxazolidinone chiral auxiliary: Steric control in the [2+2] cycloaddition of singlet oxygen through conformational alignment. J. Am. Chem. Soc. 2002, 124, 8814–8815. [Google Scholar] [CrossRef] [PubMed]
  27. Sivaguru, J.; Solomon, M.R.; Poon, T.; Jockusch, S.; Bosio, S.G.; Adam, W.; Turro, N.J. The reaction of singlet oxygen with enecarbamates: A mechanistic playground for investigating chemoselectivity, stereoselectivity, and vibratioselectivity of photooxidations. Acc. Chem. Res. 2008, 41, 387–400. [Google Scholar] [CrossRef] [PubMed]
  28. Bánez Sanz, J.; Galisteo González, D.; López Sastre, J.A.; Rodríguez Amo, J.F.; Romero-Avila García, C.; Santos García, M.; Sanz Tejedor, M.A. Photooxygenation of alditol-1-C-yl derivatives of furan with singlet oxygen. Carbohydr. Res. 1996, 289, 179–188. [Google Scholar] [CrossRef]
  29. Cermola, F.; Iesce, M.R.; Buonerba, G. Dye-Sensitized Photooxygenation of Furanosyl Furans:  Synthesis of a New Pyridazine C-Nucleoside. J. Org. Chem. 2005, 70, 6503–6505. [Google Scholar] [CrossRef]
  30. Cermola, F.; Iesce, M.R. Dye-sensitized photooxygenation of sugar-furans as synthetic strategy for novel C-nucleosides and functionalized exo-glycals. Tetrahedron 2006, 62, 10694–10699. [Google Scholar] [CrossRef]
  31. Linker, T.; Sommermann, T.; Kahlenberg, F. The addition of malonates to glycals: A general and convenient method for the synthesis of 2-C-branched carbohydrates. J. Am. Chem. Soc. 1997, 119, 9377–9384. [Google Scholar] [CrossRef]
  32. Elamparuthi, E.; Linker, T. Carbohydrate-2-deoxy-2-phosphonates: Simple synthesis and horner-emmons reaction. Angew. Chem. Int. Ed. 2009, 48, 1853–1855. [Google Scholar] [CrossRef]
  33. Mai-Linde, Y.; Linker, T. Radical Clock Probes to Determine Carbohydrate Radical Stabilities. Org. Lett. 2020, 22, 1525–1529. [Google Scholar] [CrossRef] [PubMed]
  34. Zehm, D.; Fudickar, W.; Linker, T. Molecular switches flipped by oxygen. Angew. Chem. Int. Ed. 2007, 46, 7689–7692. [Google Scholar] [CrossRef] [PubMed]
  35. Klaper, M.; Fudickar, W.; Linker, T. Role of Distance in Singlet Oxygen Applications: A Model System. J. Am. Chem. Soc. 2016, 138, 7024–7029. [Google Scholar] [CrossRef] [PubMed]
  36. Fudickar, W.; Linker, T. Singlet Oxygen Release of Singlet Oxygen from Aromatic Endoperoxides by Chemical Triggers Angewandte. Angew. Chem. Int. Ed. 2018, 57, 12971–12975. [Google Scholar] [CrossRef] [PubMed]
  37. He, Y.-Q.; Fudickar, W.; Tang, J.-H.; Wang, H.; Li, X.; Han, J.; Wang, Z.; Liu, M.; Zhong, Y.-W.; Linker, T.; et al. Capture and Release of Singlet Oxygen in Coordination-Driven Self-Assembled Organoplatinum(II) Metallacycles. J. Am. Chem. Soc. 2020, 142, 2601–2608. [Google Scholar] [CrossRef] [PubMed]
  38. Wasserman, H.H.; Larsen, D.L. Formation of 1-4-endoperoxides from the dye-sensitized photooxygenation of alkyl-naphthalenes. J. Chem. Soc. Chem. Commun. 1972, 253–254. [Google Scholar] [CrossRef]
  39. Bauch, M.; Krtitschka, A.; Linker, T. Photooxygenation of oxygen-substituted naphthalenes. J. Phys. Org. Chem. 2017, 30, 1–11. [Google Scholar] [CrossRef] [Green Version]
  40. Turro, N.J.; Chow, M.F. Mechanism of thermolysis of endoperoxides of aromatic compounds. Activation parameters, magnetic field, and magnetic isotope effects. J. Am. Chem. Soc. 1981, 103, 7218–7224. [Google Scholar] [CrossRef]
  41. Aubry, J.-M.; Pierlot, C.; Rigaudy, J.; Schmidt, R. Reversible Binding of Oxygen to Aromatic Compounds. Acc. Chem. Res. 2003, 36, 668–675. [Google Scholar] [CrossRef]
  42. Fudickar, W.; Linker, T. Release of Singlet Oxygen from Organic Peroxides under Mild Conditions. ChemPhotoChem 2018, 2, 548–558. [Google Scholar] [CrossRef]
  43. Klaper, M.; Linker, T. New singlet oxygen donors based on naphthalenes: Synthesis, physical chemical data, and improved stability. Chem. Eur. J. 2015, 21, 8569–8577. [Google Scholar] [CrossRef]
  44. Klaper, M.; Linker, T. Intramolecular Transfer of Singlet Oxygen. J. Am. Chem. Soc. 2015, 137, 13744–13747. [Google Scholar] [CrossRef] [PubMed]
  45. Coppa, F.; Fontana, F.; Lazzarini, E.; Minisci, F. A New Selective Method for the Homolytic Alkylation and Carboxylation of Quinones by Monoesters of Oxalic Acid. Chem. Lett. 1992, 21, 1299–1302. [Google Scholar] [CrossRef]
  46. Fujii, S.; Shimizu, A.; Takeda, N.; Oguchi, K.; Katsurai, T.; Shirakawa, H.; Komai, M.; Kagechika, H. Systematic synthesis and anti-inflammatory activity of ω-carboxylated menaquinone derivatives—Investigations on identified and putative vitamin K2 metabolites. Bioorg. Med. Chem. 2015, 23, 2344–2352. [Google Scholar] [CrossRef] [PubMed]
  47. Schmidt, R.R. New Methods for the Synthesis of Glycosides and Oligosaccharides—Are There Alternatives to the Koenigs-Knorr Method? Angew. Chem. Int. Ed. Engl. 1986, 25, 212–235. [Google Scholar] [CrossRef]
  48. Tietze, L.F.; Schmuck, K.; Schuster, H.J.; Müller, M.; Schuberth, I. Synthesis and biological evaluation of prodrugs based on the natural antibiotic duocarmycin for use in ADEPT and PMT. Chem. Eur. J. 2011, 17, 1922–1929. [Google Scholar] [CrossRef]
  49. Beckhaus, H.-D. 𝒮f Parameters—A Measure of the Front Strain of Alkyl Groups. Angew. Chem. Int. Ed. Engl. 1978, 17, 593–594. [Google Scholar] [CrossRef]
  50. Engelhardt, U.; Sarkar, A.; Linker, T. Efficient enantioselective total synthesis of (-)-epipodophyllotoxin. Angew. Chem. Int. Ed. 2003, 42, 2487–2489. [Google Scholar] [CrossRef]
  51. Sasaoka, M.; Hart, H. Endoperoxides of Naphthalenes. Synthesis and Reactions of Substituted 2,3-Epoxynaphthalene 1,4-Endoperoxides. J. Org. Chem. 1979, 44, 368–374. [Google Scholar] [CrossRef]
  52. Bunge, A.; Hamann, H.-J.; McCalmont, E.; Liebscher, J. Enantioselective epoxidation of 2-substituted 1,4-naphthoquinones using gem-dihydroperoxides. Tetrahedron Lett. 2009, 50, 4629–4632. [Google Scholar] [CrossRef]
  53. Fioroni, G.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. Epoxidation of α,β-unsaturated ketones in water. An environmentally benign protocol. Green Chem. 2003, 5, 425–428. [Google Scholar] [CrossRef]
  54. Ban, L.; Mrksich, M. On-Chip Synthesis and Label-Free Assays of Oligosaccharide Arrays. Angew. Chem. Int. Ed. 2008, 47, 3396–3399. [Google Scholar] [CrossRef] [PubMed]
Molecules 26 00804 sch001 550
Scheme 1. Reversible reaction of naphthalenes 1 with singlet oxygen to endoperoxides 2.
Scheme 1. Reversible reaction of naphthalenes 1 with singlet oxygen to endoperoxides 2.
Molecules 26 00804 sch001
Molecules 26 00804 sch002 550
Scheme 2. Synthesis of carbohydrate-substituted naphthalenes 1b–f from naphthoquinone 3b.
Scheme 2. Synthesis of carbohydrate-substituted naphthalenes 1b–f from naphthoquinone 3b.
Molecules 26 00804 sch002
Molecules 26 00804 g001 550
Figure 1. 1H-NMR spectra (500 MHz, 6–8 ppm) of the crude photooxygenation products of carbohydrate-substituted naphthalenes 2b–f (major isomer red, minor isomer green).
Figure 1. 1H-NMR spectra (500 MHz, 6–8 ppm) of the crude photooxygenation products of carbohydrate-substituted naphthalenes 2b–f (major isomer red, minor isomer green).
Molecules 26 00804 g001
Molecules 26 00804 g002 550
Figure 2. Characteristic NOE interactions in EPOs 1S,4R-2f and 1R,4S-2f.
Figure 2. Characteristic NOE interactions in EPOs 1S,4R-2f and 1R,4S-2f.
Molecules 26 00804 g002
Molecules 26 00804 g003 550
Figure 3. Calculated energetically minimized structures of EPOs 1S,4R-2f and 1R,4S-2f. Carbon atoms are marked black; oxygen atoms are marked red; hydrogen atoms are marked grey; blue, green, and yellow indicate the distinct NOE interactions (compare Figure 2).
Figure 3. Calculated energetically minimized structures of EPOs 1S,4R-2f and 1R,4S-2f. Carbon atoms are marked black; oxygen atoms are marked red; hydrogen atoms are marked grey; blue, green, and yellow indicate the distinct NOE interactions (compare Figure 2).
Molecules 26 00804 g003
Molecules 26 00804 g004 550
Figure 4. Proposed conformations of naphthalenes 1c–f and preferred attack of 1O2.
Figure 4. Proposed conformations of naphthalenes 1c–f and preferred attack of 1O2.
Molecules 26 00804 g004
Molecules 26 00804 sch003 550
Scheme 3. Transformation of EPO 1S,4R-2f into enantiomerically pure epoxide 2S,3R-8.
Scheme 3. Transformation of EPO 1S,4R-2f into enantiomerically pure epoxide 2S,3R-8.
Molecules 26 00804 sch003
Molecules 26 00804 g005 550
Figure 5. HPLC separation of epoxide 8 on chiral phase. (A) racemate 8 and (B) epoxide 2S,3R-8. 2R,3S isomer is marked green; 2S,3R isomer is marked red.
Figure 5. HPLC separation of epoxide 8 on chiral phase. (A) racemate 8 and (B) epoxide 2S,3R-8. 2R,3S isomer is marked green; 2S,3R isomer is marked red.
Molecules 26 00804 g005
Table
Table 1. Photooxygenation of naphthalenes 1b–f to endoperoxides 2b–f 1.
Table 1. Photooxygenation of naphthalenes 1b–f to endoperoxides 2b–f 1.
Molecules 26 00804 i001
EntryNaphthalene 1RTemperature, Conversion 2t1/2 (20 °C) 2 3dr 1S,4R-2:1R,4S-2 2
11bH20 °C, <5%2 min–
21bH−70 °C, >98%2 min–
31cMe−70 °C, >98%7 min90:10
41dEt−70 °C, >98%9 min91:9
51eiPr−70 °C, >98%48 min89:11
61ftBu−70 °C, >98%>4 h 451:49 5
1 Reactions were performed on a 0.15 mmol NMR scale. For procedure and conditions, see Materials and Methods. 2 Determined by NMR (500 MHz) of the crude products. 3 Determined by UV measurements. 4 For 77 min at 60 °C. 5 On a larger 1.0 mmol scale, diastereomeric EPOs 2f could be separated by column chromatography and isolated in 46% and 41% in analytically pure form.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Bauch, M.; Fudickar, W.; Linker, T. Stereoselective [4+2] Cycloaddition of Singlet Oxygen to Naphthalenes Controlled by Carbohydrates. Molecules 2021, 26, 804. https://doi.org/10.3390/molecules26040804

AMA Style

Bauch M, Fudickar W, Linker T. Stereoselective [4+2] Cycloaddition of Singlet Oxygen to Naphthalenes Controlled by Carbohydrates. Molecules. 2021; 26(4):804. https://doi.org/10.3390/molecules26040804

Chicago/Turabian Style

Bauch, Marcel, Werner Fudickar, and Torsten Linker. 2021. "Stereoselective [4+2] Cycloaddition of Singlet Oxygen to Naphthalenes Controlled by Carbohydrates" Molecules 26, no. 4: 804. https://doi.org/10.3390/molecules26040804

Article Metrics

Back to TopTop