Stereoselective [4+2] cycloaddition of singlet oxygen to naphthalenes controlled by carbohydrates

Article abstract of DOI:10.3390/molecules26040804

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.

Full text of DOI:10.3390/molecules26040804

molecules
Article
Stereoselective [4+2] Cycloaddition of Singlet Oxygen to
Naphthalenes Controlled by Carbohydrates
Marcel Bauch, Werner Fudickar and Torsten Linker *
Department of Chemistry, University of Potsdam, Karl-Liebknecht-Street 24-25, 14476 Golm, Germany;
marcel.potsdam@gmail.com (M.B.); wfudicka@uni-potsdam.de (W.F.)
* Correspondence: linker@uni-potsdam.de; Tel.: +49-331-977-5212
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
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
calculations. Finally, we could transfer the chiral information from a pure endoperoxide to an epoxide,
ꢀꢁꢂꢃꢄꢅꢆ
which was isolated after cleavage of the sugar chiral auxiliary in enantiomerically pure form.
Citation: Bauch, M.; Fudickar, W.;
Linker, T. Stereoselective [4+2]
Keywords: singlet oxygen; photooxygenation; naphthalenes; carbohydrates; stereoselectivity; auxil-
Cycloaddition of Singlet Oxygen to
iary control; [4+2] cycloaddition
Naphthalenes Controlled by
Carbohydrates. Molecules 2021, 26,
804. https://doi.org/10.3390/
molecules26040804
1. Introduction
Singlet oxygen (1O2) is an excited state of molecular oxygen and has been used for
Academic Editor: Axel G. Griesbeck
Received: 13 January 2021
various oxidations, in biology, or medical applications [
reactive species is short [ ], depending on the solvent [ ] or the biological environment [
it can react with high regio- [ ] and stereoselectivity [ ]. It was the pioneering work of
Adam, who discovered that OH groups can control the diastereoselectivity in ene reac-
tions [ 10]. Later on, the influence
] or [4+2] cycloadditions of 1O2 to naphthalenes [
of other functional groups on photooxygenations has been investigated [ 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 -hydroxylation of aldehydes and ketones was realized by organocatalysis with mod-
erate to good ee (enantiomeric excess) [14 16], ene reactions or cycloadditions proceed less
1]. Although the lifetime of this
Accepted: 2 February 2021
Published: 4 February 2021
2
3
4],
5
6
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
7
,8
9,
6,
,
α
–
successfully. Thus, asymmetrically modified zeolites [17], chiral salts [18], or chiral sensi-
tizers [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].
Copyright:
© 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Another possibility to control the face-selectivity of singlet oxygen attack are chiral aux-
iliaries. 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
Molecules 2021, 26, 804. https://doi.org/10.3390/molecules26040804
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 804
2 of 17
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 [28–30].
Based on our experience in carbohydrate chemistry [31
we became interested in a combination of both research topics and in sugar-substituted
naphthalenes
(Scheme 1). The advantage of such arenes is that they react with 1O2 by a
–33] and acene oxidations [34–37],
1
[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
R2 on the kinetics of such reactions [43] and could establish an intramolecular transfer of
1O2 [44]. However, carbohydrate-substituted naphthalenes 1b
were hitherto unknown,
–42]. We investigated the influence of substituents
–
f
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.
Scheme 1. Reversible reaction of naphthalenes 1 with singlet oxygen to endoperoxides 2.
2. Results and Discussion
The synthesis of carbohydrate-substituted naphthalenes 1b
quinone (3b), an inexpensive and easily available precursor. Addition of alkyl radicals,
generated by decarboxylation of acids , afforded substituted naphthoquinones 3c 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 , which were
directly used for the next step without purification, because of their oxidation lability.
Finally, Schmidt’s trichloroacetimidate 47 48] gave best results for glycosylations, and
–f started from 1,4-naphtho-
4
–f
5
6
[ ,
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
Indeed, we repeated the reaction at
,
−
41], which is especially fast with alkoxy groups [39].
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

Molecules 2021, 26, 804
3 of 17
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.
Scheme 2. Synthesis of carbohydrate-substituted naphthalenes 1b–f from naphthoquinone 3b.
Table 1. Photooxygenation of naphthalenes 1b–f to endoperoxides 2b–f 1.
Temperature,
◦
Entry Naphthalene 1
R
t1/2 (20 C) 2 3
dr 1S,4R-2:1R,4S-2 2
Conversion 2
◦
1
2
3
4
5
6
1b
1b
1c
1d
1e
1f
H
H
Me
Et
iPr
tBu
20 C, <5%
2 min
2 min
7 min
9 min
48 min
>4 h 4
–
–
◦
−70 C, >98%
◦
−70 C, >98%
90:10
91:9
89:11
51:49 5
◦
−70 C, >98%
◦
−70 C, >98%
◦
−70 C, >98%
1 Reactions were performed on a 0.15 mmol NMR scale. For procedure and conditions, see Materials and Methods.
2
3
4
Determined by NMR (500 MHz) of the crude products. Determined by UV measurements. 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.
After the successful oxidation of naphthalene 1b (Table 1, entry 2), we next inves-
tigated the photooxygenations of the alkyl-substituted derivatives 1c
conditions (entries 3–6). For all substrates, the conversion was complete after 2 h, and
we observed EPOs 2c as sole products in the NMR of the crude reaction mixture at low
temperature (for detailed NMR spectra, see Supplementary Materials). Again, thermoly-
sis of all EPOs proceeded completely reversible, and the parent naphthalenes 1c were
–f under the same
–
f
–
f
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

Molecules 2021, 26, 804
4 of 17
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 naphtha-
lene 1b, the two arene planes are identical, and only one EPO 2b can be formed (entry 2).
However, for all other substrates 1c
affording two diastereomers 1S,4R-
high stereoselectivities of about 9:1 to the corresponding EPOs 2c
–
2
f
, singlet oxygen can attack from two different faces,
and 1R,4S- . Indeed, naphthalenes 1c reacted with
(entries 3–5). Surpris-
2
–e
–e
ingly, 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 respon-
sible 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.
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 2021, 26, 804
5 of 17
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.
Figure 2. Characteristic NOE interactions in EPOs 1S,4R-2f and 1R,4S-2f.
To further support the observed NOESY interactions, we conducted theoretical calcula-
tions 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.
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 2021, 26, 804
6 of 17
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].
Figure 4. Proposed conformations of naphthalenes 1c–f and preferred attack of 1O2.
Finally, because our structural assignment was hitherto only based on NOESY mea-
surements and calculations, we wanted to determine the absolute configurations unequiv-
ocally. 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 per-
oxide 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].

Molecules 2021, 26, 804
7 of 17
Scheme 3. Transformation of EPO 1S,4R-2f into enantiomerically pure epoxide 2S,3R-8.
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 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- gave a single peak (B). Therefore, we could
8
8
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.
Figure 5. HPLC separation of epoxide
green; 2S,3R isomer is marked red.
8 on chiral phase. (A) racemate 8 and (B) epoxide 2S,3R-8. 2R,3S isomer is marked
3. Materials and Methods
3.1. Chemicals and Instrumentation
Melting points were determined using a Mel-Temp from Electrothermal. TLC was
1
performed using TLC Silica gel 60 F254 aluminum sheets from Merck. H-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
acetate 10:1. All starting materials were used as purchased without further purification.
×
3.00 mm, 5 µm), eluent hexane/ethyl
Trichloroacetimidate gluco-6 was synthesized according to the literature [54].

Molecules 2021, 26, 804
8 of 17
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 (50 mmol, 2 equiv.) were dissolved in a 1:1 mixture
4
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
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
×
50 mL), and
chromatography (PE/EtOAc 10:1) to obtain the naphthoquinones 3c
–
f
in analytically
pure form.
◦
2-Methyl-1,4-naphthoquinone 3c. Obtained as a yellow solid (1.76 g, 41%). m.p. = 106–108 C.
Rf = 0.23 (PE/EtOAc 10:1). H-NMR (500 MHz, CD2Cl2):
1
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):
= 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)
δ
,
3292 (w), 2956 (m), 2920 (m), 1621 (s), 1588 (m), 1464 (m), 1329 (m), 1300 (s), 1245 (m),
−1
1143 (m), 1061 cm (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-naphthoquinone 3d. Obtained as a yellow solid (2.35 g, 50%). m.p. = 83–84 ◦C.
1
Rf = 0.27 (PE/EtOAc 10:1). H-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-naphthoquinone 3e. Obtained as a yellow solid (3.21 g, 64%). m.p. = 43–44 ◦C.
1
Rf = 0.34 (PE/EtOAc 10:1). H-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-naphthoquinone 3f. Obtained as a yellow solid (3.89 g, 73%). m.p. = 66–67 ◦C.
1
Rf = 0.42 (PE/EtOAc 10:1). H-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),
−1
1127 cm (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.

Molecules 2021, 26, 804
9 of 17
3.3. Synthesis of Carbohydrate-Substituted Naphthalenes 1
In short, 1,4-Naphthoquinone (5 mmol) was dissolved in EtOAc (15 mL) and an
3
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
molecular sieves (4 Å), and a solution of trichloroacetimidate
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
5
was dissolved in dry dichloromethane (50 mL),
6
(4.93 g, 10 mmol) in dry
−
·
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)-naphthalene 1b. Obtained as a colorless
◦
solid (2.923 g, 76%). m.p. = 169–171 C. Rf = 0.18 (PE/EtOAc 1:1). [α]2D4
=
−
67 (c 1.00,
1
CHCl3). H-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)-naphthalene 1c. Obtained as a
colorless solid (2.994 g, 72%). m.p. = 216–217 ◦C. Rf = 0.17 (PE/EtOAc 1:1). [α]2D4 = −34 (c
1
1.00, CHCl3). H-NMR (600 MHz, CD2Cl2):
δ = 1.88 (s, 3H; 6-OAc), 1.99 (s, 3H; 4-OAc),
2.03 (s, 3H; 20-OAc), 2.03 (s, 3H; 3-OAc), 2.04 (s, 3H; 30-OAc), 2.05 (s, 3H; 40-OAc), 2.08
(s, 3H; 60-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, 50-H), 4.17
(dd, J = 12.2, 5.1 Hz, 1H; 6b-H), 4.22 (dd, J = 12.3, 2.5 Hz, 1H; 6a0-H), 4.28 (dd, J = 12.3,
5.8 Hz, 1H; 6b0-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; 40-H), 5.26 (d, J = 7.8 Hz, 1H; 10-H), 5.30 (dd, J = 9.8, 9.4 Hz, 1H;
3-H), 5.38 (dd, J = 9.8, 9.3 Hz, 1H; 30-H), 5.44 (dd, J = 9.8, 8.1 Hz, 1H; 2-H), 5.45 (dd, J = 9.8
,
7.8 Hz, 1H; 20-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 (0q;
0
0
0
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-60), 68.8 (d; C-4), 68.9 (d; C-40), 71.4 (d; C-20), 72.1
(C-5), 72.2 (d; C-2), 72.5 (d; C-50), 72.7 (d; C-30), 73.1 (d; C-3), 99.9 (d; C-10), 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-20), 169.8 (s; OAc-4), 169.8 (s; OAc-4), 170.3 (s; OAc-30), 170.4 (s;
OAc-3), 170.5 (s; OAc-6), 170.7 ppm (s; OAc-60). 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

Molecules 2021, 26, 804
10 of 17
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)-naphthalene 1d. Obtained as a
colorless solid (3.155 g, 74%). m.p. = 218–219 ◦C. Rf = 0.22 (PE/EtOAc 1:1). [α]2D3 = −28 (c
1
1.01, CHCl3). H-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; 20-OAc), 2.03 (s, 3H; 3-OAc), 2.04 (s, 3H; 30-OAc),
2.05 (s, 3H; 40-OAc), 2.07 (s, 3H; 60-OAc), 2.19 (s, 3H; 2-OAc), 2.88 (q, J = 7.6 Hz, 2H; CH2),
3.55 (ddd, J = 10.0, 5.0, 20.6 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; 6a0-H), 4.26 (dd, J = 12.3, 5.7 Hz, 1H; 6b0-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; 40-H), 5.26 (d, J = 7.8 Hz, 1H; 10-H),
0
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; 20-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). 13C0-NMR (150 MHz, CD2Cl2):
0
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-40), 20.9 (q; OAc-60), 21.0 (q; OAc-2), 23.5 (t; CH2), 62.0 (t; C-6), 62.6 (t; C-60),
68.8 (d; C-4), 68.8 (d; C-40), 71.4 (d; C-20), 72.2 (C-5), 72.2 (d; C-2), 72.7 (d; C-50), 72.7 (d;
C-30), 73.2 (d; C-3), 100.0 (d; C-10), 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-20), 169.8 (s; OAc-2), 169.8 (s;
OAc-40), 169.8 (s; OAc-4), 170.3 (s; OAc-30), 170.4 (s; OAc-3), 170.6 (s; OAc-6), 170.8 ppm
(s; OAc-60). 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)-naphthalene 1e. Obtained as a
colorless solid (3.375 g, 74%). m.p. = 219–220 ◦C. Rf = 0.27 (PE/EtOAc 1:1). [α]2D3 = −26
1
(c 1.01, CHCl3). H-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; 20-OAc, 30-OAc), 2.05 (s, 3H; 40-OAc), 2.06 (s, 3H; 60-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, 50-H), 4.13 (dd, J = 12.3, 4.8 Hz, 1H;
6b-H), 4.22 (dd, J = 12.4, 2.8 Hz, 1H; 6a0-H), 4.25 (dd, J = 12.4, 5.2 Hz, 1H; 6b0-H), 5.005 (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; 10-H), 5.30 (dd, J = 9.8, 9.4 Hz, 1H; 3-H), 5.38 (dd, J = 9.7, 9.3 Hz,
1H; 30-H), 5.44 (dd, J = 9.7, 7.8 Hz, 1H; 20-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-20, OAc-30), 20.9 (q; OAc-40), 21.0 (q; OAc-60), 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-60), 68.7 (d; C-4), 68.7 (d; C-40), 71.3 (d;
C-20), 72.2 (C-5), 72.2 (d; C-2), 72.7 (d; C-30), 72.7 (d; C-50), 73.2 (d; C-3), 100.0 (d; C-10),
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-20), 169.7 (s; OAc-2), 169.8 (s; OAc-4), 169.8 (s; OAc-40), 170.3 (s; OAc-30),
170.5 (s; OAc-3), 170.6 (s; OAc-6), 170.8 ppm (s; OAc-60). 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)-naphthalene 1f. Obtained as a
colorless solid (3.106 g, 71%). m.p. = 230–231 ◦C. Rf = 0.31 (PE/EtOAc 1:1). [α]2D4
=
−
28
1
(c 1.01, CHCl3). H-NMR (600 MHz, CD2Cl2):
δ = 1.49 (s, 9H; t-Bu), 1.93 (s, 3H; 6-OAc),

Molecules 2021, 26, 804
11 of 17
1.98 (s, 3H; 40-OAc), 2.03 (s, 3H; 30-OAc), 2.04 (s, 3H; 3-OAc), 2.05 (s, 3H; 4-OAc), 2.05 (s,
3H; 20-OAc), 2.06 (s, 3H; 60-OAc), 2.22 (s, 3H; 2-OAc), 3.49 (ddd, J = 10.0, 4.2, 2.5 Hz, 1H;
0
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; 6a0-H), 4.24 (dd, J = 12.4, 5.2 Hz,
1H; 6b0-H), 5.17 (dd, J = 10.1, 9.4 Hz, 1H; 4-H), 5.18 (dd, J = 10.0, 9.3 Hz, 1H; 40-H), 5.24 (d,
J = 7.8 Hz, 1H; 10-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
0
0
(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
0
0
0
0
(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-60), 68.6 (d; C-4), 68.7 (d; C-40), 71.3 (d; C-20),
72.0 (C-5), 72.3 (d; C-2), 72.7 (d; C-30), 72.8 (d; C-50), 73.1 (d; C-3), 100.2 (d; C-10), 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-20), 169.8 (s; OAc-4), 169.9 (s; OAc-40), 170.3 (s; OAc-3), 170.4 (s;
OAc-30), 170.6 (s; OAc-6), 170.8 ppm (s; OAc-60). 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 mg) in CD2Cl2 (3.0 mL) was cooled to
the solution, and the mixture was irradiated externally with a sodium lamp (400 W) for
1
(0.15 mmol) and sensitizer tetraphenylporphyrin (TPP,
−
70 ◦C, oxygen was slowly bubbled through
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) w◦ere 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.
1
Endoperoxide 2b. Rf = 0.56 (PE/EtOAc 3:1). H-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; 50-H), 4.01 (dd, J = 12.5, 2.4 Hz, 1H; 6a’-H), 4.06 (dd, J = 12.5, 2.1 Hz, 1H;
0
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, 10-H, 2-H, 20-H, 3-H, 30-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-60), 66.5 (d; C-4),
66.8 (d; C-40), 69.4 (d; C-20), 70.1 (d; C-2), 70.9 (d; C-30), 71.2 (d; C-3), 71.5 (d; C-50), 71.6 (d;
C-5), 96.5 (d; C-10), 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.
1
Endoperoxide 2c. Rf = 0.51 (PE/EtOAc 3:1). H-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;

Molecules 2021, 26, 804
12 of 17
OAc), 2.00 (s, 3H; OAc), 2.04 (s, 3H; 60-OAc), 2.06 (s, 3H; OAc), 2.15 (s, 3H; 6-OAc), 3.82
0
(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; 40-H), 5.15 (dd, J = 9.8, 9.7 Hz, 1H; 4-H), 5.13–5.33 (m, 6H; 2-H,
1-H, 20-H, 10-H, 3-H, 30-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 0.6 (q; 2 x OAc), 20.6 (q; 3 x OAc), 20.7 (q; OAc), 20.8 (q; OAc), 21.0 (q;
0
0
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
0
0
(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).
1
Endoperoxide 2d. Rf = 0.44 (PE/EtOAc 2:1). H-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; 60-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; 50-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, 40-H), 5.16 (dd, J = 9.8, 7.8 Hz, 1H; 2-H), 5.17–5.26 (m, 4H; 20-H, 30-H, 1-H, 10-H); 5.31
0
(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; 20x 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-20), 70.6 (d; C-2), 71.7 (d; C-3‘), 71.8 (d; C-3), 72.3 (d; C-50), 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‘).
1
Endoperoxide 2e. Rf = 0.47 (PE/EtOAc 2:1). H-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; 60-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; 50-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; 40-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; 20-H), 5.22–5.27
(m, 3H; 3-H, 1-H, 10-H); 5.31 (dd, J = 9.7, 9.6 Hz, 1H; 30-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-60),
62.6 (t; C-6), 67.9 (d; C-4‘), 68.1 (d; C-4), 70.2 (d; C-20), 70.7 (d; C-2), 71.8 (d; C-3‘), 71.9 (d;
0
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‘).

Molecules 2021, 26, 804
13 of 17
1
Endoperoxide 1S,4R-2f. Rf = 0.19 (PE/EtOAc 1:1). [α]2D4 = +13 (c 1.04, CHCl3). H-NMR
(600 MHz, CD2Cl2):
δ
= 1.15 (s, 9H; tBu), 1.98 (s, 3H; 30-OAc), 1.99 (s, 3H; 2-OAc), 2.01 (s,
3H; 3-OAc), 2.02 (2s, 6H; 60-OAc, 40-OAc), 2.03 (s, 3H; 4-OAc), 2.06 (s, 3H; 20-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; 50-H), 4.15–4.18 (m, 2H; 6a0-H, 6b0-H), 4.21–4.28 (m, 2H; 6a-H, 6b-H), 5.09 (dd, J = 10.1,
0
0
0
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,
0
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;
0
δ = 20.8 (q; OAc-3 ), 20.8 (q; OAc-2), 20.8 (q; OAc-3),
8-ArH). 13C-NMR (150 MHz, CD2Cl2):
20.8 (q; OAc-60), 20.9 (q; OAc-40), 20.9 (q; OAc-4), 21.0 (q; OAc-20), 21.0 (q; OAc-6), 28.4 (q;
tBu), 35.4 (s; tBu), 62.8 (t; C-60), 63.0 (t; C-6), 68.7 (d; C-40), 68.7 (d; C-4), 70.9 (d; C-2), 71.4
(d; C-20), 72.4 (d; C-3), 72.9 (d; C-50), 72.9 (d; C-30), 72.9 (d; C-5), 97.1 (d; C-10), 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;
0
0
0
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-60). 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.
1
Endoperoxide 1R,4S-2f. Rf = 0.12 (PE/EtOAc 1:1). [α]2D4
(600 MHz, CD2Cl2):
=
−
2.5 (c 1.01, CHCl3). H-NMR
δ
= 1.15 (s, 9H; tBu), 1.98 (s, 3H; 4-OAc), 1.99 (s, 3H; 20-OAc), 2.00
(s, 3H; 3-OAc), 2.00 (s, 3H; 30-OAc), 2.01 (s, 3H; 40-OAc), 2.03 (s, 3H; 6-OAc), 2.05 (s, 3H;
0
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,
0
0
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; 40-H), 5.23 (dd, J = 9.7, 8.0 Hz, 1H; 20-H),
0
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;
30-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).
0 0
δ = 20.7 (q; OAc-4), 20.7 (3q; OAc-2 , OAc-3, OAc-4 ), 20.8 (q;
13C-NMR (150 MHz, CD2Cl2):
OAc-30), 20.8 (q; OAc-6), 20.8 (q; OAc-60), 20.9 (q; OAc-2), 28.2 (q; tBu), 35.5 (s; tBu), 61.9 (t;
C-6), 62.0 (t; C-60), 68.2 (d; C-40), 68.6 (d; C-4), 71.6 (d; C-20), 71.8 (d; C-2), 72.5 (d; C-5), 72.8
(2d; C-50, C-30), 73.2 (d; C-3), 97.1 (d; C-1), 97.2 (d; C-10), 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-20), 169.7 (s;
OAc-40), 169.7 (s; OAc-4), 170.3 (s; OAc-3), 170.3 (s; OAc-30), 170.7 (s; OAc-6), 170.7 ppm
(s; OAc-60). 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
at different temperatures and observing the increasing absorption band of the correspond-
ing naphthalene at 290–320 nm. The singlet oxygen yield was determined by trapping
2 were determined by measuring UV/VIS spectra
1
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

Molecules 2021, 26, 804
14 of 17
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.
1
Rf = 0.16 (PE/EtOAc 1:1). [α]2D4 = +66 (c 0.99, CHCl3). H-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;
0
0
0
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; 10-H, 2-H, 20-H, 30-H, 4-H, 40-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-20), 71.4 (s; ArC-2), 72.4 (d; C-3), 72.6 (d; C-50), 73.0 (d; C-30), 73.1 (d; C-5), 97.1
(d; C-10), 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-60). 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.
0
0
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).
◦
1
M.p. = 61–63 C. Rf = 0.81 (PE/EtOAc 1:1). [α]2D5
=
−
22 (c 1.00, CHCl3). H-NMR
t
(400 MHz, CDCl3):
δ
= 1.23 (s, 9H; Bu), 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 naph-
thalenes 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 re-
markable 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 naph-
thoquinone 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

Molecules 2021, 26, 804
15 of 17
the photooxygenations, and are finally cleaved, the concept of a chiral auxiliary controlled
[4+2] cycloaddition of singlet oxygen to naphthalenes has been realized.
1
Supplementary Materials: The following are available online, S2–S5: H- and 13C-NMR spectra of
1
naphthoquinones
3
, S6–S10: H- and 13C-NMR spectra of carbohydrate-substituted naphthalenes
1,
S11–S17: H- and 13C-NMR spectra of endoperoxides
2f, S20–S21: H- and 13C-NMR spectra of epoxides 7 and 8, S22–S30: theoretical calculations.
2, S18–S19: NOESY spectra of endoperoxides
1
1
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.
2.
3.
Gorman, A.A.; Rodgers, M.A.J. Singlet molecular oxygen. Chem. Soc. Rev. 1981, 10, 205–231. [CrossRef]
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. [CrossRef]
4.
5.
6.
7.
8.
9.
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. [CrossRef]
Stratakis, M.; Orfanopoulos, M. Regioselectivity in the Ene Reaction of Singlet Oxygen with Alkenes. Tetrahedron 2000, 56,
1595–1615. [CrossRef]
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. [CrossRef]
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. [CrossRef]
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. [CrossRef]
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. [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. [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. [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. [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. [CrossRef]
14. Sundén, H.; Engqvist, M.; Casas, J.; Ibrahem, I.; Córdova, A. Direct amino acid catalyzed asymmetric
molecular oxygen. Angew. Chem. Int. Ed. 2004, 43, 6532–6535. [CrossRef]
α oxidation of ketones with
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. [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. [CrossRef]
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. [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.
[CrossRef]
19. Griesbeck, A.G.; Miranda, M.A.; Uhlig, J. Sweet chiral porphyrins as singlet oxygen sensitizers for asymmetric Type II photooxy-
genation. Photochem. Photobiol. Sci. 2011, 10, 1431–1435. [CrossRef] [PubMed]

Molecules 2021, 26, 804
16 of 17
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. [CrossRef] [PubMed]
21. Adam, W.; Brünker, H.-G.; Nestler, B. Photooxygenation of 2-alkenyl substituted chiral oxazolines: Stereochemical evi-
dence favouring the cis effect in the regioselective ene reaction of singlet oxygen with α,β-unsaturated carbonyl derivatives.
Tetrahedron Lett. 1991, 32, 1957–1960. [CrossRef]
22. Dussault, P.H.; Woller, K.R.; Hillier, M.C. Stereoselective dioxygenation of enoates. Tetrahedron 1994, 50, 8929–8940. [CrossRef]
23. Fudickar, W.; Vorndran, K.; Linker, T. Auxiliary controlled singlet-oxygen ene reactions of cyclohexenes. Tetrahedron 2006, 62,
10639–10646. [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. [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.
[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. [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 enecarba-
mates: A mechanistic playground for investigating chemoselectivity, stereoselectivity, and vibratioselectivity of photooxidations.
Acc. Chem. Res. 2008, 41, 387–400. [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.
[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. [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. [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. [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. [CrossRef]
33. Mai-Linde, Y.; Linker, T. Radical Clock Probes to Determine Carbohydrate Radical Stabilities. Org. Lett. 2020, 22, 1525–1529.
[CrossRef] [PubMed]
34. Zehm, D.; Fudickar, W.; Linker, T. Molecular switches flipped by oxygen. Angew. Chem. Int. Ed. 2007, 46, 7689–7692. [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. [CrossRef] [PubMed]
,
36. Fudickar, W.; Linker, T. Singlet Oxygen Release of Singlet Oxygen from Aromatic Endoperoxides by Chemical Triggers Ange-
wandte. Angew. Chem. Int. Ed. 2018, 57, 12971–12975. [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. [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. [CrossRef]
39. Bauch, M.; Krtitschka, A.; Linker, T. Photooxygenation of oxygen-substituted naphthalenes. J. Phys. Org. Chem. 2017, 30, 1–11.
[CrossRef]
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. [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. [CrossRef]
42. Fudickar, W.; Linker, T. Release of Singlet Oxygen from Organic Peroxides under Mild Conditions. ChemPhotoChem 2018, 2,
548–558. [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. [CrossRef]
44. Klaper, M.; Linker, T. Intramolecular Transfer of Singlet Oxygen. J. Am. Chem. Soc. 2015, 137, 13744–13747. [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. [CrossRef]

Molecules 2021, 26, 804
17 of 17
46. Fujii, S.; Shimizu, A.; Takeda, N.; Oguchi, K.; Katsurai, T.; Shirakawa, H.; Komai, M.; Kagechika, H. Systematic synthesis and
anti-inflammatory activity of -carboxylated menaquinone derivatives—Investigations on identified and putative vitamin K2
ω
metabolites. Bioorg. Med. Chem. 2015, 23, 2344–2352. [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. [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. [CrossRef]
49. Beckhaus, H.-D.
[CrossRef]
S
f Parameters—A Measure of the Front Strain of Alkyl Groups. Angew. Chem. Int. Ed. Engl. 1978, 17, 593–594.
50. Engelhardt, U.; Sarkar, A.; Linker, T. Efficient enantioselective total synthesis of (-)-epipodophyllotoxin. Angew. Chem. Int. Ed.
2003, 42, 2487–2489. [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. [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. [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. [CrossRef]
54. Ban, L.; Mrksich, M. On-Chip Synthesis and Label-Free Assays of Oligosaccharide Arrays. Angew. Chem. Int. Ed. 2008, 47,
3396–3399. [CrossRef] [PubMed]