An ingenious method for the determination of the relative and absolute configurations of compounds containing aryl-glycerol fragments by1H NMR spectroscopy

Article abstract of DOI:10.1039/d0ra09712h

A concise method was established to determine the relative and absolute configurations of aryl-glycerols that depend on the chemical shift differences (Δδ) of the diastereotopic methylene protons (H-3) by¹H NMR spectroscopy. When using DMSO-d₆as the preferred solvent, thethreoconfiguration corresponded to a larger Δδ_H3a-H3bvalue (>0.15 ppm), whereas theerythroconfiguration (<0.07 ppm) corresponded to a smaller value. Furthermore, the absolute configurations were determined with the aid of a simple acylation reaction through camphanoyl chloride. In thethreoenantiomers, the Δδvalue of the 1R,2Rconfiguration was <0.15 ppm, and that of the 1S,2Sconfiguration was >0.20 ppm. In theerythroenantiomers, the Δδvalue of 1R,2Swas >0.09 ppm, and that of 1S,2Rwas <0.05 ppm. Remarkably, this empirical rule is invalid in CDCl₃. In addition, this method was also verified by a quantum¹H NMR calculation.

Full text of DOI:10.1039/d0ra09712h

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An ingenious method for the determination of the
relative and absolute configurations of compounds
containing aryl-glycerol fragments by H NMR
Cite this: RSC Adv., 2021, 11, 8107
1
spectroscopy†
Xu Zhang, Kai-Zhou Lu, Hai-Wei Yan, Zi-Ming Feng, Ya-Nan Yang,
*
Jian-Shuang Jiang and Pei-Cheng Zhang
A concise method was established to determine the relative and absolute configurations of aryl-glycerols
that depend on the chemical shift differences (Dd) of the diastereotopic methylene protons (H-3) by 1H
NMR spectroscopy. When using DMSO-d6 as the preferred solvent, the threo configuration
corresponded to a larger DdH3a–H3b value (>0.15 ppm), whereas the erythro configuration (<0.07 ppm)
corresponded to a smaller value. Furthermore, the absolute configurations were determined with the aid
of a simple acylation reaction through camphanoyl chloride. In the threo enantiomers, the Dd value of
the 1R,2R configuration was <0.15 ppm, and that of the 1S,2S configuration was >0.20 ppm. In the
erythro enantiomers, the Dd value of 1R,2S was >0.09 ppm, and that of 1S,2R was <0.05 ppm.
Remarkably, this empirical rule is invalid in CDCl3. In addition, this method was also verified by
a quantum 1H NMR calculation.
Received 16th November 2020
Accepted 11th February 2021
DOI: 10.1039/d0ra09712h
rsc.li/rsc-advances
Aryl-glycerols (AGs), a kind of 1,2,3-prim,sec,sec-triols, are
frequent in natural products such as phenylpropanoids and
lignans6–15 and are important intermediates in many chemical
Introduction
Chiral alcohols, such as chiral secondary alcohols, prim,sec-
diols, sec,sec-diols and 1,2,3-prim,sec,sec-triols, are ubiquitous in
natural products and synthetic products. The assignment of
their relative and absolute congurations is always a chal-
lenging task. Because of the difficulty of growing crystals of
these compounds and the lack of distinct Cotton effects in their
electronic circular dichroism (ECD) spectra, NMR spectroscopy
is suitable for this purpose and is readily available compared
with other methods. For instance, the absolute congurations
of chiral secondary alcohols were determined using Mosher's
method by 1H NMR spectroscopy;1 the relative congurations of
some sec,sec-diols were assigned using a JBCA (J-based cong-
uration analysis) method2 or by comparison of their 13C-Dd
behaviors in a chiral bidentate NMR solvent.3 We have also
developed two approaches to (1) discriminate the threo and
erythro congurations of vicinal diol in polyacetylene glycosides
syntheses.16–21 Due to the conformational exibility of the triol
chain in AGs, determining the relative and absolute congura-
tions is signicantly challenging. Recently, Mosher's method
was developed to assign the absolute conguration of AGs by
comparing the 1H NMR data of the tris-(R)- and the tris-(S)-MPA
ester derivatives with those of the AGs.22,23 However, the
inability to prepare tris-MPA ester derivatives for trace
compounds and the complex rules governing the comparison of
the DdRS(H-1) and jDdRS
ꢀ DdRSH(1)j of AGs, to some extent,
H(2)
have limited the application of this method. For some naturally
occurring AGs, the regular DdC1–C2 parameters have been used
to differentiate only the threo and erythro relative
3
by the JHH value using acetic acid-d4/D2O as the solvent;4 and
(2) determine the absolute congurations of 2-hydroxy phenyl-
ethanoid glycosides (prim,sec-diol derivatives) by the chemical
shi differences (Dd) of the diastereotopic methylene protons.5
State Key Laboratory of Bioactive Substance and Function of Natural Medicines,
Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union
Medical College, Beijing 100050, People's Republic of China. E-mail: pczhang@imm.
ac.cn
Fig. 1 Structures of compounds M1–M4.
† Electronic supplementary information (ESI) available: 1D NMR, 2D NMR, and
HRMS spectra. See DOI: 10.1039/d0ra09712h
© 2021 The Author(s). Published by the Royal Society of Chemistry
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Fig. 2 Structures of compounds 1–11.
congurations.9,15 However, we found that this rule is not summarize this phenomenon, two pairs of 1-phenylpropane-
applicable to AGs without substituent groups on the benzene 1,2,3-triol enantiomers were prepared (M1–M4) through the
ring. Therefore, a new reliable method to determine the relative hydrolysis of (2R,3R)-3-phenyl-2-oxiranemethanol and (2S,3S)-3-
and absolute congurations of AGs is a worthwhile task.
phenyl-2-oxiranemethanol (Fig. 1). The 1H NMR spectra of
compounds M1 and M4 in methanol-d4 were recorded. Obvi-
ously, the DdH3a–H3b (0.14 ppm) value of methylene protons in
the threo conguration was remarkably larger than the corre-
sponding value (0.06 ppm) in the erythro conguration (Fig. 3).
Considering that deuterated solvents have a major impact on
Results and discussion
Our recent study found that the threo and erythro congurations
of H-7 and H-8 in 8,40-oxyneolignans can be discriminated by
1
the chemical shis of methylene protons, the H NMR spectra
1
the values of DdH9a–H9b of methylene protons in H NMR spec-
of compounds M1 and M4 were recorded in other deuterated
solvents, acetone-d6, pyridine-d5, DMSO-d6, and CDCl3, as
shown in Fig. 3. Similarly, in the threo congurations, the
DdH3a–H3b values of methylene protons were 0.12 in acetone-d6,
0.15 in pyridine-d5, and 0.21 in DMSO-d6. In the erythro
congurations, the DdH3a–H3b values of methylene protons were
0.00 in acetone-d6, 0.00 in pyridine-d5, and 0.06 in DMSO-d6.
Remarkably, there was no obvious difference in CDCl3 (threo:
troscopy.24 When we determined the congurations of a pair of
threo syringylglycerol enantiomers (1 and 2) obtained from the
1
Arnebia euchroma, a careful comparison of the H NMR spec-
troscopic data of 1 in methanol-d4 with the corresponding data
in erythro syringylglycerol in the literature showed that there
were signicant differences.9 The value of DdH3a–H3b of methy-
lene protons in 1 is 0.13 ppm, while the value is only 0.07 ppm
in erythro syringylglycerol. Surprisingly, this result is similar to
the rule in 8,40-oxyneolignans. For AGs without large steric
hindrance groups, can the DdH3a–H3b values of the methylene
groups reect their relative stereochemistry? To explore and
Table 1 DdH3a–H3b values (ppm) of the AGs 1–11 in different solvents
(1H NMR 500 MHz)
No.
dH3a
dH3b
DdH3a–H3b
Solvent
Relative conf.
Threo
1 & 2
3 & 4
3.50
3.49
3.55
3.56
4.27
3.39
3.64
3.61
4.39
3.42
3.68
3.67
3.42
3.47
3.31
3.52
3.35
3.37
3.40
3.39
3.42
4.09
3.15
3.59
3.61
4.39
3.37
3.65
3.63
3.42
3.34
3.14
3.38
3.18
0.13
0.09
0.16
0.14
0.18
0.24
0.05
0.00
0.00
0.05
0.03
0.04
0.00
0.13
0.17
0.14
0.17
Methanol-d4
Acetone-d6
Methanol-d4
Acetone-d6
Pyridine-d5
DMSO-d6
Methanol-d4
Acetone-d6
Pyridine-d5
DMSO-d6
Methanol-d4
Acetone-d6
DMSO-d6
Methanol-d4
DMSO-d6
Threo
5 & 6
7 & 8
Erythro
Erythro
9 & 10
Threo
Threo
11
Methanol-d4
DMSO-d6
Fig. 3 Influence of different deuterated solvents on the DdH3a–H3b
values of M1 and M4 (1H NMR 500 MHz).
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Scheme 1 The acylation reaction.
Fig. 4 Influence of different deuterated solvents on the DdH3a–H3b values of M1a–M4a (1H NMR 500 MHz).
0.09 ppm; erythro: 0.07 ppm). In addition, the chemical shi
values of methylene protons in the erythro conguration were absolute congurations of a pair of enantiomers. Considering
obviously larger than those in the threo conguration. the conformational exibility of the triol chain in AGs, the
Then, a more challenging task is how to determine the
To further conrm the accuracy and reliability of the method introduction of a chiral auxiliary agent bearing a larger steric
and investigate the inuence of different substitution groups on hindrance group may be an efficient approach. Camphanoyl
the benzene ring, 1-(4-bromophenyl)propane-1,2,3-triol (3–6) chloride, a acylating agent containing two special stereogenic
and 1-(4-nitrophenyl)propane-1,2,3-triol (7 and 8) were synthe- centers, is frequently utilized to determine enantiomeric purity
sized through the Sharpless asymmetric epoxidation and in organic synthesis and its derivatives was also used to assign
hydrolysis reaction (Fig. 2).25 As expected, larger DdH3a–H3b absolute congurations of chiral alcohols by NMR.26,27 It made
values of methylene protons appeared in the threo congura- molecules more rigid due to its steric hindrance in conforma-
tions (3–4), and smaller DdH3a–H3b values of methylene protons tional studies. These features inspired us to thoroughly inves-
appeared in the erythro congurations (5–8). Additionally, three tigate the relationship between the chemical shi differences of
natural products, threo-1-C-guaiacylglycerol (9 and 10), obtained methylene protons and the absolute congurations of mono-
from bamboo juice, and compound 11, obtained from Cortex camphanoyl AGs.
Lycii, were also in accordance with the general trends in
Accordingly, acylation reactions (Scheme 1) were carried out
methanol-d4 and DMSO-d6 (Fig. 2). Thus, the relative congu- using (ꢀ)-1S,4R-camphanoyl chloride and two pairs of 1-phenyl
ration of AGs can be determined from the DdH3a–H3b values of glycerol enantiomers M1–M4 as raw materials, and four prod-
methylene protons of the 1H NMR spectra in methanol-d4, ucts (M1a–M4a) were successfully obtained. Their 1H NMR
acetone-d6, pyridine-d5, and DMSO-d6; DMSO-d6 is the preferred spectra were measured in several deuterated solvents, including
solvent (Table 1).
methanol-d4, DMSO-d6, acetone-d6, pyridine-d5, and CDCl3. To
our delight, in methanol-d4 and DMSO-d6, the DdH3a–H3b values
Fig. 5 DdH3a–H3b values (ppm) of the acylation products.
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of methylene protons showed obvious differences in the threo spectra were recorded with a Bruker 500 MHz (Bruker-Biospin,
and erythro congurations. In the threo enantiomers, the DdH3a– Billerica, MA, USA). HRESIMS reports were obtained from an
values of methylene protons in M1a (1R,2R) were 0.15 and Agilent 6520 HPLC-Q-TOF (Agilent Technologies, Waldbronn,
H3b
0.15, respectively, while the DdH3a–H3b values in M2a (1S,2S) Germany) and Q Exactive Focus LCMSMS (Thermo Scientic,
were 0.28 and 0.32, respectively (Fig. 4). In the erythro system, MA, USA). Preparative HPLC separations were performed using
the DdH3a–H3b values of methylene protons in M3a (1R,2S) were a Shimadzu LC-10AT with an ODS-A column (250 mm ꢁ 10
0.09 and 0.15, respectively, while the DdH3a–H3b values in M4a mm, 5 mm; YMC Corp., Kyoto, Japan). An Agilent 1200 series
(1S,2R) were 0.03 and 0.00, respectively. The chemical shi system with an Apollo C 18 column (250 mm ꢁ 4.6 mm, 5 mm;
differences were high enough to discriminate the absolute Alltech Corp., KY, USA) was used for HPLC-DAD analysis. All
conguration, especially when using DMSO-d6 as the solvent. reactions were magnetically stirred with a DF-101S magnetic
However, in the other three deuterated solvents, acetone-d6, stirrer (Hengfengchangwei Technology Co. Ltd, Beijing, China).
CDCl3, and pyridine-d5, the DdH3a–H3b values were irregular. Commercially available reagents were used without further
These results suggested that the anisotropic effect of campha- purication unless otherwise stated. All reactions were moni-
noyl could be efficiently and selectively space oriented toward tored by TLC with silica gel pre-coated GF254 plates and HPLC-
the methylene protons of mono-camphanoyl AGs in methanol- DAD.
d4 and DMSO-d6. To further verify the reliability of the method,
derivatives 1a–8a, and 10a were also successfully synthesized. As
Structure characterization and synthesis procedures
expected, the rule still applies in methanol-d4 and DMSO-d6
(Fig. 5). Furthermore, the theoretical 1H NMR calculation of
(2S,3S)-3-Phenyl-2-oxiranemethanol and (2R,3R)-3-phenyl-2-
oxiranemethanol. The asymmetric epoxidation was carried out
according to the Sharpless asymmetric Epoxidation. Colorless
oil; the specic rotations were [a]2D0 ꢀ47 (c 0.1 methanol)
and [a]2D0 +70 (c 0.1 methanol), respectively; 1H-NMR (500
MHz, methanol-d4): d 7.27–7.35 (5H, one mono-substituted
benzene ring system), 3.87 (1H, dd, J ¼ 12.5, 3.0 Hz), 3.83
(1H, d, J ¼ 2.0 Hz), 3.67 (1H, dd, J ¼ 12.5, 5.5 Hz), 3.15 (1H,
m); 13C-NMR (125 MHz, CDCl3): d 136.8, 128.7, 128.7, 128.5,
125.9, 125.9, 62.5, 61.3, 55.7; HRESIMS m/z 151.0754 [M +
H]+ (calcd for C9H11O2 151.0753).
M1a–M4a was carried out by GIAO NMR calculation method in
DMSO (the detailed procedure see ESI†).28 The calculated
results were better match with the experimental data (R2
$
0.995) (Fig. 6). The calculated DdH3a–H3b values were M1a: 0.08,
M2a: 0.37, M3a: 0.72, and M4a: 0.06, respectively. This result
veried our method was also reliable by quantum chemical
calculation. These results conrmed that camphanoyl chloride
is a suitable pure chiral derivatizing agent to assign the absolute
conguration of AGs.
A solution of (2R,3R)-3-phenyl-2-oxiranemethanol (100 mg,
0.6 mmol) and acetic acꢂid (0.5 ml) in acetonitrile was stirred by
rotary evaporator at 55 C until the solution was dry. Through
the analysis of HPLC, the (2R,3R)-3-phenyl-2-oxiranemethanol
Experimental section
General experimental procedures
The optical rotations were recorded with a RUDOLPH automa- was completely hydrolyzed. The residue was separated by
tic V polarimeter (RUDOLPH, Hackettstown, NJ, USA). The NMR preparative HPLC (MeOH/H2O, 25 : 75, v\v, HOAc, 0.1%) to
Fig. 6 Linear correlation plots of predicted versus experimental 1H NMR chemical shifts.
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afford M1 (45 mg) and M4 (50 mg). The hydrolysis procedure of under reduced pressure and purication of the residue by
(2S,3S)-3-phenyl-2-oxiranemethanol was same as the above. The preparative HPLC, eluting with 40% acetonitrile/H2O, gave the
residue was separated by preparative HPLC (MeOH/H2O, M1a 8.7 mg. Colorless oil; 1H-NMR (500 MHz, methanol-d4):
25 : 75, v\v, HOAc, 0.1%) to afford M2 and M3. Compounds M1– d 7.27–7.42 (5H, one mono-substituted benzene ring system),
M4 are known compounds and they were identied by 4.65 (1H, d, J ¼ 5.5 Hz), 4.21 (1H, dd, J ¼ 11.5, 3.5 Hz), 4.06 (1H,
comparing their spectral data with those of the known dd, J ¼ 11.5, 7.0 Hz), 3.95 (1H, m), 2.47 (1H, m), 2.03 (1H, m),
compounds.22
1.96 (1H, m), 1.62 (1H, m), 1.09 (3H, s), 1.09 (3H, s), 0.94 (3H, s).
(1R,2R)-1-Phenylpropane-1,2,3-triol
and
(1S,2S)-1- 1H-NMR (500 MHz, DMSO-d6): d 7.23–7.38 (5H, one mono-
phenylpropane-1,2,3-triol (M1 and M2). Colorless oil; the substituted benzene ring system), 4.56 (1H, t, J ¼ 5.0 Hz), 4.10
specic rotations were [a]2D0 ꢀ39 (c 0.1 methanol) and [a]D20 +33 (c (1H, dd, J ¼ 11.0, 3.5 Hz), 3.95 (1H, dd, J ¼ 11.0, 7.5 Hz), 3.80
1
0.1 methanol), respectively. H-NMR (500 MHz, methanol-d4): (1H, m), 2.35 (1H, m), 1.97 (1H, m), 1.90 (1H, m), 1.54 (1H, m),
d 7.25–7.40 (5H, one mono-substituted benzene ring system), 1.01 (3H, s), 1.00 (3H, s), 0.83 (3H, s). 1H-NMR (500 MHz,
4.63 (1H, d, J ¼ 5.5 Hz), 3.69 (1H, m), 3.50 (1H, dd, J ¼ 11.5, 4.0 acetone-d6): d 7.26–7.45 (5H, one mono-substituted benzene
Hz), 3.36 (1H, dd, J ¼ 11.5, 6.0 Hz). 1H-NMR (500 MHz, acetone- ring system), 4.73 (1H, t, J ¼ 5.0 Hz), 4.24 (1H, dd, J ¼ 11.5, 3.5
d6): d 7.23–7.41 (5H, one mono-substituted benzene ring Hz), 4.11 (1H, dd, J ¼ 11.5, 7.0 Hz), 3.98 (1H, m), 2.46 (1H, m),
system), 4.68 (1H, d, J ¼ 5.5 Hz), 3.65 (1H, m), 3.51 (1H, dd, J ¼ 2.01 (1H, m), 1.95 (1H, m), 1.60 (1H, m), 1.09 (3H, s), 1.05 (3H,
11.0, 3.5 Hz), 3.39 (1H, dd, J ¼ 11.5, 5.5 Hz). 1H-NMR (500 MHz, s), 0.92 (3H, s). 1H-NMR (500 MHz, pyridine-d5): d 7.80 (2H, d, J
pyridine-d5): d 7.84 (2H, d, J ¼ 7.5 Hz), 7.40 (2H, t, J ¼ 7.5 Hz), ¼ 7.5 Hz), 7.42 (2H, d, J ¼ 7.5 Hz), 7.32 (1H, t, J ¼ 7.5 Hz), 5.22
7.30 (1H, t, J ¼ 7.5 Hz), 5.39 (1H, d, J ¼ 5.5 Hz), 4.39 (1H, m), 4.24 (1H, d, J ¼ 5.0 Hz), 4.75 (1H, dd, J ¼ 11.0, 7.5 Hz), 4.70 (1H, dd, J
1
(1H, dd, J ¼ 11.0, 4.5 Hz), 4.09 (1H, dd, J ¼ 11.0, 6.0 Hz). H- ¼ 11.0, 4.0 Hz), 4.52 (1H, m), 2.47 (1H, m), 1.99 (1H, m), 1.82
NMR (500 MHz, DMSO-d6): d 7.19–7.34 (5H, one mono- (1H, m), 1.57 (1H, m), 1.06 (3H, s), 1.05 (3H, s), 1.02 (3H, s). 1H-
substituted benzene ring system), 4.53 (1H, t, J ¼ 5.0 Hz), 3.48 NMR (500 MHz, CDCl3): d 7.30–7.37 (5H, one mono-substituted
(1H, m), 3.36 (1H, m), 3.15 (1H, m). 1H-NMR (500 MHz, CDCl3): benzene ring system), 4.68 (1H, d, J ¼ 7.0 Hz), 4.25 (1H, dd, J ¼
d 7.28–7.33 (5H, one mono-substituted benzene ring system), 11.5, 3.5 Hz), 4.11 (1H, dd, J ¼ 11.5, 6.5 Hz), 3.98 (1H, m), 2.41
4.66 (1H, d, J ¼ 5.5 Hz), 3.76 (1H, brs), 3.54 (1H, brd, J ¼ 11.0 (1H, m), 2.02 (1H, m), 1.92 (1H, m), 1.69 (1H, m), 1.11 (3H, s),
Hz), 3.46 (1H, brd, J ¼ 11.0 Hz). 13C-NMR (125 MHz, CDCl3): 1.05 (3H, s), 0.96 (3H, s). 13C-NMR (125 MHz, methanol-d4):
d 140.6, 128.6, 128.6, 128.2, 126.8, 126.8, 76.2, 74.8, 63.2; d 180.3, 168.7, 142.9, 129.3, 129.3, 128.8, 127.9, 127.9, 92.9, 75.6,
HRESIMS refer to compounds M3 and M4.
(1R,2S)-1-Phenylpropane-1,2,3-triol
74.5, 67.6, 56.0, 55.4, 31.5, 29.9, 17.1, 17.0, 9.9; HRESIMS m/z
(1S,2R)-1- 371.1465 [M + Na]+ (calcd for C19H24O6Na 371.1458).
and
phenylpropane-1,2,3-triol (M3 and M4). Colorless oil; the
(2S,3S)-2,3-Dihydroxy-3-phenylpropyl(1S,4R)-4,7,7-trimethyl-
specic rotations were [a]2D0 ꢀ47 (c 0.1 methanol) and [a]2D0 +27 (c 3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate
(M2a).
The
1
0.1 methanol), respectively. H-NMR (500 MHz, methanol-d4): synthesis procedure of M2a was same with the M1a. Colorless
d 7.24–7.41 (5H, one mono-substituted benzene ring system), oil; 1H-NMR (500 MHz, methanol-d4): d 7.27–7.41 (5H, one
4.61 (1H, d, J ¼ 6.5 Hz), 3.75 (1H, m), 3.66 (1H, dd, J ¼ 11.5, 3.5 mono-substituted benzene ring system), 4.67 (1H, d, J ¼ 6.0 Hz),
Hz), 3.60 (1H, dd, J ¼ 11.5, 6.5 Hz); 1H-NMR (500 MHz, acetone- 4.27 (1H, dd, J ¼ 11.0, 3.5 Hz), 3.99 (1H, dd, J ¼ 11.0, 6.5 Hz),
d6): d 7.21–7.41 (5H, one mono-substituted benzene ring 3.94 (1H, m), 2.49 (1H, m), 2.04 (1H, m), 1.97 (1H, m), 1.63 (1H,
1
system), 4.67 (1H, d, J ¼ 4.0 Hz), 3.73 (1H, m), 3.61 (2H, overlap). m), 1.11 (3H, s), 1.09 (3H, s), 0.94 (3H, s). H-NMR (500 MHz,
1H-NMR (500 MHz, pyridine-d5): d 7.88 (2H, d, J ¼ 8.0 Hz), 7.40 DMSO-d6): d 7.23–7.37 (5H, one mono-substituted benzene ring
(2H, t, J ¼ 8.0 Hz), 7.30 (1H, t, J ¼ 8.0 Hz), 5.35 (1H, d, J ¼ 6.0 system), 4.56 (1H, d, J ¼ 5.0 Hz), 4.18 (1H, dd, J ¼ 11.0, 3.5 Hz),
Hz), 4.50 (1H, m), 4.42 (2H, overlap). 1H-NMR (500 MHz, DMSO- 3.85 (1H, dd, J ¼ 11.0, 7.0 Hz), 3.80 (1H, m), 2.38 (1H, m), 1.97
d6): d 7.19–7.34 (5H, one mono-substituted benzene ring (1H, m), 1.90 (1H, m), 1.54 (1H, m), 1.01 (3H, s), 1.00 (3H, s),
1
system), 4.42 (1H, overlap), 3.51 (1H, m), 3.44 (1H, m), 3.38 (1H, 0.83 (3H, s). H-NMR (500 MHz, acetone-d6): d 7.25–7.45 (5H,
m). 1H-NMR (500 MHz, CDCl3): d 7.30–7.39 (5H, one mono- one mono-substituted benzene ring system), 4.73 (1H, d, J ¼ 5.5
substituted benzene ring system), 4.89 (1H, d, J ¼ 5.0 Hz), Hz), 4.29 (1H, dd, J ¼ 11.0, 4.0 Hz), 4.03 (1H, dd, J ¼ 11.0, 6.5
3.85 (1H, m), 3.74 (1H, dd, J ¼ 11.0, 5.5 Hz), 3.67 (1H, dd, J ¼ Hz), 3.97 (1H, m), 2.49 (1H, m), 2.02 (1H, m), 1.96 (1H, m), 1.60
11.0, 3.5 Hz). 13C-NMR (125 MHz, CDCl3): d 140.4, 128.8, 128.8, (1H, m), 1.10 (3H, s), 1.05 (3H, s), 0.92 (3H, s). 1H-NMR (500
128.3, 126.3, 126.3, 76.1, 74.6, 63.1; HRESIMS m/z 191.0679 [M + MHz, pyridine-d5): d 7.80 (2H, d, J ¼ 8.0 Hz), 7.42 (2H, d, J ¼ 8.0
Na]+ (calcd for C9H12O3Na 191.0679).
Hz), 7.32 (1H, t, J ¼ 8.0 Hz), 5.24 (1H, d, J ¼ 5.0 Hz), 4.80 (1H, dd,
J ¼ 11.0, 3.0 Hz), 4.62 (1H, dd, J ¼ 11.0, 7.0 Hz), 4.53 (1H, m),
(2R,3R)-2,3-Dihydroxy-3-phenylpropyl(1S,4R)-4,7,7-
trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate (M1a). 2.50 (1H, m), 2.01 (1H, m), 1.84 (1H, m), 1.58 (1H, m), 1.06 (3H,
Compound M1 (10 mg, 0.06 mmol) solution in dry CH2Cl2 or s), 1.06 (3H, s), 1.02 (3H, s). 1H-NMR (500 MHz, CDCl3): d 7.30–
THF was added to a solution of camphanic acid chloride (13 mg, 7.38 (5H, one mono-substituted benzene ring system), 4.68 (1H,
0.06 mmol), EDCI (11.4 mg, 0.06 mmol) and DMAP (3.6 mg, 0.03 d, J ¼ 6.5 Hz), 4.25 (1H, dd, J ¼ 11.5, 3.5 Hz), 4.08 (1H, dd, J ¼
mmol) at 0 ꢂC with the protection of argon gas. The reaction was 11.5, 6.5 Hz), 3.98 (1H, m), 2.42 (1H, m), 2.02 (1H, m), 1.92 (1H,
stirred at 0 ꢂC for 1 h and was detected by TLC. Then, the m), 1.68 (1H, m), 1.11 (3H, s), 1.06 (3H, s), 0.97 (3H, s). 13C-NMR
reaction was quenched by dropwise addition of H2O. The (125 MHz, methanol-d4): d 180.3, 168.8, 142.8, 129.3, 129.3,
suspension was extracted with CH2Cl2. Removal of the solvent
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128.8, 127.9, 127.9, 92.9, 75.6, 74.5, 67.6, 56.0, 55.4, 31.5, 30.0, m), 1.11 (3H, s), 1.04 (3H, s), 0.95 (3H, s). 13C-NMR (125 MHz,
17.1, 17.0, 9.9; HRESIMS refer to compound M1a.
(2S,3R)-2,3-Dihydroxy-3-phenylpropyl(1S,4R)-4,7,7-
methanol-d4): d 180.3, 168.9, 143.2, 129.2, 129.2, 128.6, 128.1,
128.1, 93.0, 75.8, 74.2, 67.8, 56.0, 55.4, 31.5, 30.0, 17.1, 17.0, 9.9;
trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate (M3a). HRESIMS refer to compound M1a.
The synthesis procedure of M3a was same with the M1a.
(1R,2R)-1-(4-Hydroxy-3,5-dimethoxyphenyl)propane-1,2,3-
Colorless oil; 1H-NMR (500 MHz, methanol-d4): d 7.26–7.42 (5H, triol and (1S,2S)-1-(4-hydroxy-3,5-dimethoxyphenyl)propane-
one mono-substituted benzene ring system), 4.61 (1H, d, J ¼ 6.5 1,2,3-triol (1 and 2). Colorless oil; the specic rotations were
Hz), 4.42 (1H, dd, J ¼ 11.5, 3.0 Hz), 4.32 (1H, dd, J ¼ 11.5, 7.0 [a]2D0 ꢀ100 (c 0.1 methanol) and [a]D20 +70 (c 0.1 methanol),
Hz), 3.95 (1H, m), 2.49 (1H, m), 2.04 (1H, m), 1.97 (1H, m), 1.62 respectively. 1H-NMR (500 MHz, methanol-d4): d 6.68 (2H, brs),
(1H, m), 1.10 (3H, s), 1.09 (3H, s), 0.94 (3H, s). 1H-NMR (500 4.53 (1H, d, J ¼ 6.0 Hz), 3.67 (1H, m), 3.50 (1H, dd, J ¼ 11.5, 4.0
MHz, DMSO-d6):
d
7.23–7.37 (5H, one mono-substituted Hz), 3.37 (1H, dd, J ¼ 11.5, 6.5 Hz). 1H-NMR (500 MHz, acetone-
benzene ring system), 4.46 (1H, dd, J ¼ 6.5, 4.5 Hz), 4.35 (1H, d6): d 6.69 (2H, brs), 4.56 (1H, d, J ¼ 6.0 Hz), 3.62 (1H, m), 3.49
dd, J ¼ 11.5, 3.0 Hz), 4.20 (1H, dd, J ¼ 11.5, 7.0 Hz), 3.74 (1H, m), (1H, dd, J ¼ 11.0, 4.0 Hz), 3.40 (1H, dd, J ¼ 11.0, 6.0 Hz). 13C-
2.39 (1H, m), 1.98 (1H, m), 1.90 (1H, m), 1.55 (1H, m), 1.03 (3H, NMR (125 MHz, methanol-d4): d 149.1, 149.1, 135.9, 134.1,
s), 1.00 (3H, s), 0.83 (3H, s). 1H-NMR (500 MHz, acetone-d6): 105.0, 105.0, 77.6, 75.6, 64.2, 56.7, 56.7; HRESIMS m/z 267.0839
d 7.24–7.44 (5H, one mono-substituted benzene ring system), [M + Na]+ (calcd for C11H16O6Na 267.0837). Compounds 1 and 2
4.72 (1H, dd, J ¼ 6.5, 4.5 Hz), 4.39 (1H, dd, J ¼ 11.5, 3.0 Hz), 4.33 are known compounds and they were identied by comparing
(1H, dd, J ¼ 11.5, 7.0 Hz), 4.01 (1H, m), 2.48 (1H, m), 2.00 (1H, their spectral data with those of the known compounds.8
m), 1.94 (1H, m), 1.59 (1H, m), 1.09 (3H, s), 1.05 (3H, s), 0.92
4-((1R,2R)-1,2-Dihydroxy-3-(((1S,4R)-4,7,7-trimethyl-3-oxo-2-
1
(3H, s). H-NMR (500 MHz, pyridine-d5): d 7.82 (2H, d, J ¼ 7.5 oxabicyclo[2.2.1]heptane-1-carbonyl)oxy)propyl)-2,6-dimethox-
Hz), 7.41 (2H, d, J ¼ 7.5 Hz), 7.31 (1H, t, J ¼ 7.5 Hz), 5.22 (1H, d, J yphenyl(1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]
¼ 6.5 Hz), 5.06 (1H, dd, J ¼ 11.5, 3.0 Hz), 4.98 (1H, dd, J ¼ 11.5, heptane-1-carboxylate (1a). Compound 1 (6 mg, 0.02 mmol)
7.0 Hz), 4.55 (1H, m), 2.49 (1H, m), 1.99 (1H, m), 1.82 (1H, m), solution in dry CH2Cl2 or THF was added to a solution of
1.57 (1H, m), 1.07 (3H, s), 1.06 (3H, s), 1.05 (3H, s). 1H-NMR (500 camphanic acid chloride (9 mg, 0.04 mmol), EDCI (7.6 mg, 0.04
MHz, CDCl3): d 7.29–7.38 (5H, one mono-substituted benzene mmol) and DMAP (2.4 mg, 0.02 mmol) at 0 ꢂC with the
ring system), 4.83 (1H, d, J ¼ 5.5 Hz), 4.34 (1H, dd, J ¼ 11.5, 7.5 protection of argon gas. The reaction was stirred at 0 ꢂC for 1 h
Hz), 4.25 (1H, dd, J ¼ 11.5, 3.0 Hz), 4.09 (1H, m), 2.40 (1H, m), and was detected by TLC. Then, the reaction was quenched by
2.00 (1H, m), 1.92 (1H, m), 1.67 (1H, m), 1.10 (3H, s), 1.04 (3H, dropwise addition of H2O. The suspension was extracted with
s), 0.95 (3H, s). 13C-NMR (125 MHz, methanol-d4): d 180.3, 168.9, CH2Cl2. Removal of the solvent under reduced pressure and
143.2, 129.2, 129.2, 128.6, 128.1, 128.1, 93.0, 75.8, 74.1, 67.8, purication of the residue by preparative HPLC, eluting with
56.0, 55.4, 31.5, 30.0, 17.1, 17.0, 9.9; HRESIMS refer to 40% acetonitrile/H2O, gave the 1a 2.9 mg. Colorless oil; 1H-NMR
compound M1a.
(500 MHz, methanol-d4): d 6.84 (2H, brs), 4.68 (1H, d, J ¼ 5.0
(2R,3S)-2,3-Dihydroxy-3-phenylpropyl(1S,4R)-4,7,7-
Hz), 4.33 (1H, dd, J ¼ 11.5, 4.0 Hz), 4.16 (1H, dd, J ¼ 11.5, 6.5
trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate (M4a). Hz), 3.97 (1H, m), 2.67 (1H, m), 2.48 (1H, m), 2.12 (2H, overlap),
The synthesis procedure of M4a was same with the M1a. 2.04 (1H, m), 1.97 (1H, m), 1.70 (1H, m), 1.63 (1H, m), 1.22 (3H,
Colorless oil; 1H-NMR (500 MHz, methanol-d4): d 7.26–7.42 (5H, s), 1.14 (3H, s), 1.10 (3H, s), 1.09 (3H, s), 1.08 (3H, s), 0.97 (3H, s);
one mono-substituted benzene ring system), 4.62 (1H, d, J ¼ 7.0 HRESIMS m/z 605.2593 [M + H]+ (calcd for C31H41O12 605.2593).
Hz), 4.38 (1H, dd, J ¼ 11.5, 6.5 Hz), 4.35 (1H, dd, J ¼ 11.5, 3.5
4-((1S,2S)-1,2-Dihydroxy-3-(((1S,4R)-4,7,7-trimethyl-3-oxo-2-
Hz), 3.96 (1H, m), 2.49 (1H, m), 2.03 (1H, m), 1.97 (1H, m), 1.62 oxabicyclo[2.2.1]heptane-1-carbonyl)oxy)propyl)-2,6-dimethox-
(1H, m), 1.10 (3H, s), 1.09 (3H, s), 0.94 (3H, s). 1H-NMR (500 yphenyl(1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]
MHz, DMSO-d6):
d 7.22–7.36 (5H, one mono-substituted heptane-1-carboxylate (2a). Compound 2 (4.4 mg, 0.018 mmol)
benzene ring system), 4.47 (1H, dd, J ¼ 6.5, 4.5 Hz), 4.26 (2H, solution in dry CH2Cl2 or THF was added to a solution of
overlap), 3.75 (1H, m), 2.38 (1H, m), 1.97 (1H, m), 1.90 (1H, m), camphanic acid chloride (7.8 mg, 0.036 mmol), EDCI (6.8 mg,
1.54 (1H, m), 1.01 (3H, s), 1.00 (3H, s), 0.84 (3H, s). 1H-NMR (500 0.036 mmol) and DMAP (2.2 mg, 0.018 mmol) at 0 C with the
ꢂ
MHz, acetone-d6): d 7.24–7.44 (5H, one mono-substituted protection of argon gas. The reaction was stirred at 0 ꢂC for 1 h
benzene ring system), 4.72 (1H, dd, J ¼ 6.0, 4.5 Hz), 4.38 (1H, and was detected by TLC. Then, the reaction was quenched by
dd, J ¼ 11.5, 7.0 Hz), 4.33 (1H, dd, J ¼ 11.5, 3.5 Hz), 4.01 (1H, m), dropwise addition of H2O. The suspension was extracted with
2.47 (1H, m), 2.00 (1H, m), 1.94 (1H, m), 1.59 (1H, m), 1.09 (3H, CH2Cl2. Removal of the solvent under reduced pressure and
1
s), 1.05 (3H, s), 0.92 (3H, s). H-NMR (500 MHz, pyridine-d5): purication of the residue by preparative HPLC, eluting with
d 7.82 (2H, d, J ¼ 7.5 Hz), 7.41 (2H, d, J ¼ 7.5 Hz), 7.31 (1H, t, J ¼ 55% methanol/H2O, gave the 2a 2.0 mg. Colorless oil; 1H-NMR
7.5 Hz), 5.22 (1H, d, J ¼ 7.0 Hz), 5.06 (1H, dd, J ¼ 11.5, 7.0 Hz), (500 MHz, methanol-d4): d 6.82 (2H, brs), 4.69 (1H, d, J ¼ 5.0
4.98 (1H, dd, J ¼ 11.5, 3.0 Hz), 4.55 (1H, m), 2.50 (1H, m), 1.99 Hz), 4.36 (1H, dd, J ¼ 11.5, 4.0 Hz), 4.13 (1H, dd, J ¼ 11.5, 6.5
(1H, m), 1.83 (1H, m), 1.57 (1H, m), 1.07 (3H, s), 1.06 (3H, s), Hz), 3.97 (1H, m), 2.67 (1H, m), 2.49 (1H, m), 2.12 (2H, overlap),
1
1.04 (3H, s). H-NMR (500 MHz, CDCl3): d 7.30–7.38 (5H, one 2.02 (2H, overlap), 1.70 (1H, m), 1.63 (1H, m), 1.22 (3H, s), 1.14
mono-substituted benzene ring system), 4.84 (1H, d, J ¼ 5.5 Hz), (3H, s), 1.11 (3H, s), 1.09 (3H, s), 1.08 (3H, s), 0.94 (3H, s);
4.38 (1H, dd, J ¼ 11.5, 7.5 Hz), 4.24 (1H, dd, J ¼ 11.5, 3.0 Hz), HRESIMS m/z 605.2593 [M + H]+ (calcd for C31H41O12 605.2600).
4.08 (1H, m), 2.41 (1H, m), 2.01 (1H, m), 1.92 (1H, m), 1.68 (1H,
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((2R,3R)-3-(4-Bromophenyl)oxiran-2-yl)methanol
RSC Advances
132.0, 130.3, 130.3, 122.0, 76.5, 75.3, 64.3; HRESIMS refer to
compounds 3 and 4.
and
((2S,3S)-3-(4-bromophenyl)oxiran-2-yl)methanol. The asym-
metric epoxidation was also carried out according to the
Sharpless asymmetric Epoxidation. Colorless oil; the specic
rotations were [a]2D0 +45 (c 0.1 methanol) and [a]2D0 ꢀ25 (c 0.1
methanol), respectively. 1H-NMR (500 MHz, methanol-d4):
d 7.49 (2H, d, J ¼ 8.5 Hz), 7.22 (2H, d, J ¼ 8.5 Hz), 3.85 (1H, dd, J
¼ 12.5, 3.0 Hz), 3.83 (1H, d, J ¼ 1.5 Hz), 3.67 (1H, dd, J ¼ 12.5,
4.5 Hz), 3.13 (1H, m); 13C-NMR (125 MHz, methanol-d4): d 138.2,
132.6, 132.6, 128.7, 128.7, 122.8, 63.9, 62.6, 56.2; HRESIMS m/z
228.9859 [M + H]+ (calcd for C9H10O2Br 228.9858).
(2R,3R)-3-(4-Bromophenyl)-2,3-dihydroxypropyl(1S,4R)-
4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate
(3a). The synthesis procedure of 3a was same with the M1a.
Colorless oil; 1H-NMR (500 MHz, methanol-d4): d 7.50 (2H, d, J
¼ 8.5 Hz), 7.35 (2H, d, J ¼ 8.5 Hz), 4.66 (1H, d, J ¼ 5.0 Hz), 4.26
(1H, dd, J ¼ 11.5, 4.0 Hz), 4.11 (1H, dd, J ¼ 11.5, 7.0 Hz), 3.92
(1H, m), 2.46 (1H, m), 2.03 (1H, m), 1.97 (1H, m), 1.63 (1H, m),
1
1.09 (6H, overlap), 0.94 (3H, s). H-NMR (500 MHz, DMSO-d6):
d 7.51 (2H, d, J ¼ 8.5 Hz), 7.31 (2H, d, J ¼ 8.5 Hz), 4.56 (1H, d, J ¼
3.5 Hz), 4.12 (1H, dd, J ¼ 11.0, 3.5 Hz), 3.97 (1H, dd, J ¼ 11.0, 8.0
Hz), 3.79 (1H, m), 2.35 (1H, m), 1.97 (1H, m), 1.90 (1H, m), 1.54
(1H, m), 1.00 (6H, overlap), 0.82 (3H, s). 13C-NMR (125 MHz,
methanol-d4): d 180.3, 168.7, 142.4, 132.3, 132.3, 129.9, 129.9,
122.3, 92.9, 74.7, 74.2, 67.6, 56.1, 55.4, 31.5, 29.9, 17.1, 17.0, 9.9;
HRESIMS m/z 449.0570 [M + Na]+ (calcd for C19H23O6BrNa
449.0562).
(2S,3S)-3-(4-Bromophenyl)-2,3-dihydroxypropyl(1S,4R)-4,7,7-
trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate (4a).
The synthesis procedure of 4a was same with the M1a. Colorless
oil; 1H-NMR (500 MHz, methanol-d4): d 7.50 (2H, d, J ¼ 8.5 Hz),
7.34 (2H, d, J ¼ 8.5 Hz), 4.67 (1H, d, J ¼ 5.0 Hz), 4.31 (1H, dd, J ¼
11.5, 4.0 Hz), 4.04 (1H, dd, J ¼ 11.5, 7.0 Hz), 3.91 (1H, m), 2.48
(1H, m), 2.04 (1H, m), 1.98 (1H, m), 1.63 (1H, m), 1.10 (3H, s),
A
solution
of
((2R,3R)-3-(4-bromophenyl)oxiran-2-yl)
methanol (65 mg, 0.3 mmol) and acetic acid (0.5 ml) in aceto-
nitrile was stirred by rotary evaporator at 55 ꢂC until the solution
was dry. Through the analysis of HPLC, the ((2R,3R)-3-(4-
bromophenyl)oxiran-2-yl)methanol was completely hydrolyzed.
The residue was separated by preparative HPLC (MeOH/H2O,
45 : 55, v\v) to afford 3 (27 mg) and 6 (38 mg). The hydrolysis
procedure of ((2S,3S)-3-(4-bromophenyl)oxiran-2-yl)methanol
was same as the above. The residue was separated by prepara-
tive HPLC (MeOH/H2O, 45 : 55, v\v) to afford 4 and 5.
Compounds 3–6 are known compounds and their absolute
congurations were identied by comparing the optical rota-
tions of M1–M4.
(1R,2R)-1-(4-Bromophenyl)propane-1,2,3-triol and (1S,2S)-1-
(4-bromophenyl)propane-1,2,3-triol (3 and 4). Colorless oil; the
specic rotations were [a]2D0 ꢀ20 (c 0.1 methanol) and [a]2D0 +16 (c
1
1.09 (3H, s), 0.93 (3H, s). H-NMR (500 MHz, DMSO-d6): d 7.51
(2H, d, J ¼ 8.0 Hz), 7.31 (2H, d, J ¼ 8.0 Hz), 4.56 (1H, d, J ¼ 3.5
Hz), 4.19 (1H, dd, J ¼ 11.5, 3.5 Hz), 3.88 (1H, dd, J ¼ 11.5, 7.0
Hz), 3.79 (1H, m), 2.36 (1H, m), 1.97 (1H, m), 1.90 (1H, m), 1.54
(1H, m), 1.00 (6H, overlap), 0.82 (3H, s). 13C-NMR (125 MHz,
methanol-d4): d 180.3, 168.7, 142.4, 132.3, 132.3, 129.9, 129.9,
122.3, 92.9, 74.7, 74.1, 67.5, 56.0, 55.4, 31.5, 30.0, 17.1, 17.0, 9.9;
HRESIMS refer to compounds 3a.
(2S,3R)-3-(4-Bromophenyl)-2,3-dihydroxypropyl(1S,4R)-4,7,7-
trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate (5a).
The synthesis procedure of 5a was same with the M1a. Colorless
oil; 1H-NMR (500 MHz, methanol-d4): d 7.50 (2H, d, J ¼ 8.5 Hz),
7.34 (2H, d, J ¼ 8.5 Hz), 4.57 (1H, d, J ¼ 7.0 Hz), 4.42 (1H, dd, J ¼
11.5, 3.5 Hz), 4.31 (1H, dd, J ¼ 11.5, 7.0 Hz), 3.89 (1H, m), 2.48
(1H, m), 2.03 (1H, m), 1.98 (1H, m), 1.63 (1H, m), 1.10 (3H, s),
1
0.1 methanol), respectively. H-NMR (500 MHz, methanol-d4):
d 7.48 (2H, d, J ¼ 8.5 Hz), 7.33 (2H, d, J ¼ 8.5 Hz), 4.65 (1H, d, J ¼
5.0 Hz), 3.65 (1H, m), 3.55 (1H, dd, J ¼ 11.5, 4.5 Hz), 3.39 (1H,
dd, J ¼ 11.5, 6.5 Hz). 1H-NMR (500 MHz, acetone-d6): d 7.49 (2H,
d, J ¼ 8.5 Hz), 7.37 (2H, d, J ¼ 8.5 Hz), 4.72 (1H, t, J ¼ 4.5 Hz),
3.64 (1H, m), 3.56 (1H, m), 3.42 (1H, m). 1H-NMR (500 MHz,
pyridine-d5): d 7.71 (2H, d, J ¼ 8.5 Hz), 7.55 (2H, d, J ¼ 8.5 Hz),
5.38 (1H, d, J ¼ 5.0 Hz), 4.35 (1H, m), 4.28 (1H, dd, J ¼ 11.0, 4.5
Hz), 4.09 (1H, dd, J ¼ 11.0, 6.0 Hz). 1H-NMR (500 MHz, DMSO-
d6): d 7.48 (2H, d, J ¼ 8.5 Hz), 7.29 (2H, d, J ¼ 8.5 Hz), 4.55 (1H, t,
J ¼ 5.0 Hz), 3.46 (1H, m), 3.39 (1H, m), 3.15 (1H, m). 13C-NMR
(125 MHz, methanol-d4): d 143.0, 132.2, 132.2, 129.8, 129.8,
122.0, 77.1, 74.4, 64.1; HRESIMS m/z 268.9784 [M + Na]+ (calcd
for C9H11O3BrNa 268.9778).
1
1.09 (3H, s), 0.94 (3H, s). H-NMR (500 MHz, DMSO-d6): d 7.51
(2H, d, J ¼ 8.5 Hz), 7.30 (2H, d, J ¼ 8.5 Hz), 4.42 (1H, d, J ¼ 6.0
Hz), 4.36 (1H, dd, J ¼ 11.0, 3.0 Hz), 4.18 (1H, dd, J ¼ 11.0, 6.5
Hz), 3.69 (1H, m), 2.38 (1H, m), 1.98 (1H, m), 1.91 (1H, m), 1.55
(1H, m), 1.02 (3H, s), 1.00 (3H, s), 0.83 (3H, s). 13C-NMR (125
MHz, methanol-d4): d 180.3, 168.9, 142.7, 132.2, 132.2, 130.2,
130.2, 122.3, 93.0, 75.0, 74.0, 67.7, 56.0, 55.4, 31.5, 30.0, 17.1,
17.0, 9.9; HRESIMS refer to compounds 3a.
(1R,2S)-1-(4-Bromophenyl)propane-1,2,3-triol and (1S,2R)-1-
(4-bromophenyl)propane-1,2,3-triol (5 and 6). Colorless oil; the
specic rotations were [a]2D0 ꢀ8 (c 0.1 methanol) and [a]2D0 +12 (c
1
0.1 methanol), respectively. H-NMR (500 MHz, methanol-d4):
d 7.48 (2H, d, J ¼ 8.5 Hz), 7.33 (2H, d, J ¼ 8.5 Hz), 4.58 (1H, d, J ¼
6.5 Hz), 3.70 (1H, m), 3.64 (1H, dd, J ¼ 11.5, 4.0 Hz), 3.59 (1H,
dd, J ¼ 11.5, 6.5 Hz). 1H-NMR (500 MHz, acetone-d6): d 7.48 (2H,
d, J ¼ 8.5 Hz), 7.37 (2H, d, J ¼ 8.5 Hz), 4.65 (1H, d, J ¼ 6.5 Hz),
(2R,3S)-3-(4-Bromophenyl)-2,3-dihydroxypropyl(1S,4R)-4,7,7-
trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate (6a).
The synthesis procedure of 6a was same with the M1a. Colorless
oil; 1H-NMR (500 MHz, methanol-d4): d 7.50 (2H, d, J ¼ 8.5 Hz),
7.34 (2H, d, J ¼ 8.5 Hz), 4.57 (1H, d, J ¼ 6.5 Hz), 4.37 (1H, dd, J ¼
11.5, 4.0 Hz), 4.35 (1H, dd, J ¼ 11.5, 6.0 Hz), 3.90 (1H, m), 2.48
(1H, m), 2.03 (1H, m), 1.97 (1H, m), 1.62 (1H, m), 1.10 (3H, s),
1
3.69 (1H, m), 3.62 (2H, overlap). H-NMR (500 MHz, pyridine-
d5): d 7.74 (2H, d, J ¼ 8.5 Hz), 7.55 (2H, d, J ¼ 8.5 Hz), 5.30 (1H,
1
dd, J ¼ 5.5, 3.0 Hz), 4.42 (1H, m), 4.39 (2H, overlap). H-NMR
(500 MHz, DMSO-d6): d 7.47 (2H, d, J ¼ 8.5 Hz), 7.28 (2H, d, J
¼ 8.5 Hz), 4.41 (1H, t, J ¼ 5.0 Hz), 3.47 (1H, m), 3.42 (1H, m),
3.37 (1H, m). 13C-NMR (125 MHz, methanol-d4): d 142.9, 132.0,
1
1.09 (3H, s), 0.94 (3H, s). H-NMR (500 MHz, DMSO-d6): d 7.51
(2H, d, J ¼ 8.5 Hz), 7.30 (2H, d, J ¼ 8.5 Hz), 4.43 (1H, d, J ¼ 6.5
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Hz), 4.28 (1H, dd, J ¼ 11.5, 3.5 Hz), 4.23 (1H, dd, J ¼ 11.5, 6.5 17.0, 9.9; HRESIMS m/z 394.1496 [M + H]+ (calcd for C19H24O8N
Hz), 3.69 (1H, m), 2.37 (1H, m), 1.97 (1H, m), 1.91 (1H, m), 1.54 394.1494).
(1H, m), 1.00 (6H, overlap), 0.84 (3H, s). 13C-NMR (125 MHz,
(2R,3S)-2,3-Dihydroxy-3-(4-nitrophenyl)propyl(1S,4R)-4,7,7-
methanol-d4): d 180.3, 168.9, 142.7, 132.2, 132.2, 130.1, 130.1, trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate (8a).
122.3, 93.0, 75.1, 74.0, 67.7, 56.0, 55.4, 31.5, 30.0, 17.1, 17.0, 9.9; The synthesis procedure of 8a was same with the M1a. Colorless
HRESIMS refer to compounds 3a.
oil; 1H-NMR (500 MHz, methanol-d4): d 8.23 (2H, d, J ¼ 8.5 Hz),
((2R,3R)-3-(4-Nitrophenyl)oxiran-2-yl)methanol and ((2S,3S)- 7.66 (2H, d, J ¼ 8.5 Hz), 4.71 (1H, d, J ¼ 7.5 Hz), 4.42 (1H, dd, J ¼
3-(4-nitrophenyl)oxiran-2-yl) methanol. The asymmetric epoxi- 11.5, 4.0 Hz), 4.39 (1H, dd, J ¼ 11.5, 5.5 Hz), 3.92 (1H, m), 2.50
dation was also carried out according to the Sharpless asym- (1H, m), 2.03 (1H, m), 1.97 (1H, m), 1.62 (1H, m), 1.10 (3H, s),
1
metric Epoxidation. Colorless oil; the specic rotations were 1.09 (3H, s), 0.95 (3H, s). H-NMR (500 MHz, DMSO-d6): d 8.20
[a]2D0 +44 (c 0.1 methanol) and [a]2D0 ꢀ46 (c 0.1 methanol), (2H, d, J ¼ 9.0 Hz), 7.63 (2H, d, J ¼ 9.0 Hz), 4.59 (1H, d, J ¼ 7.0
respectively. 1H-NMR (500 MHz, methanol-d4): d 8.21 (2H, d, J ¼ Hz), 4.31 (1H, dd, J ¼ 11.5, 3.5 Hz), 4.26 (1H, dd, J ¼ 11.5, 6.5
9.0 Hz), 7.53 (2H, d, J ¼ 9.0 Hz), 4.00 (1H, d, J ¼ 2.0 Hz), 3.89 Hz), 3.74 (1H, m), 2.38 (1H, m), 1.97 (1H, m), 1.91 (1H, m), 1.54
(1H, dd, J ¼ 13.0, 3.0 Hz), 3.71 (1H, dd, J ¼ 13.0, 4.5 Hz), 3.17 (1H, m), 1.01 (3H, s), 1.00 (3H, s), 0.84 (3H, s). 13C-NMR (125
(1H, m); 13C-NMR (125 MHz, methanol-d4): d 149.1, 146.6, 127.7, MHz, methanol-d4): d 180.3, 168.9, 151.4, 148.8, 129.2, 129.2,
127.7, 124.6, 124.6, 64.5, 62.3, 55.7; HRESIMS m/z 196.0604 [M + 124.2, 124.2, 92.9, 74.9, 74.1, 67.6, 56.0, 55.4, 31.5, 30.0, 17.0,
H]+ (calcd for C9H10O4N 196.0608).
17.0, 9.9; HRESIMS refer to compound 7a.
(1R,2S)-1-(4-Nitrophenyl)propane-1,2,3-triol and (1S,2R)-1-
(1R,2R)-1-(4-Hydroxy-3-methoxyphenyl)propane-1,2,3-triol
(4-nitrophenyl)propane-1,2,3-triol (7 and 8). A solution of and (1S,2S)-1-(4-hydroxy-3-methoxyphenyl)propane-1,2,3-triol
((2R,3R)-3-(4-nitrophenyl)oxiran-2-yl)methanol (80 mg, 0.25 (9 and 10). Colorless oil; the specic rotations were [a]2D0 ꢀ19
mmol) (which was dissolved by THF) and acetic acid (0.5 ml) in (c 0.1 methanol) and [a]2D0 +23 (c 0.1 methanol), respectively. 1H-
ꢂ
water was stirred at 80 C until the solution was dry. Through NMR (500 MHz, methanol-d4): d 6.99 (1H, d, J ¼ 1.5 Hz), 6.80
the analysis of HPLC, the ((2R,3R)-3-(4-nitrophenyl)oxiran-2-yl) (1H, dd, J ¼ 8.5, 1.5 Hz), 6.76 (1H, d, J ¼ 8.5 Hz), 4.52 (1H, d, J ¼
methanol was completely hydrolyzed. The residue was sepa- 6.5 Hz), 3.86 (3H, s), 3.66 (1H, m), 3.47 (1H, dd, J ¼ 11.0, 4.0 Hz),
1
rated by chiral column on preparative HPLC (n-hexane/ 3.34 (1H, dd, J ¼ 11.0, 6.5 Hz). H-NMR (500 MHz, DMSO-d6):
isopropanol, 80 : 20, v\v) to afford 7 (50 mg) and 8 (30 mg). d 6.89 (1H, brs), 6.69 (2H, overlap), 4.38 (1H, d, J ¼ 5.0 Hz), 3.74
The hydrolysis of ((2S,3S)-3-(4-nitrophenyl)oxiran-2-yl)methanol (3H, s), 3.44 (1H, m), 3.31 (1H, dd, J ¼ 11.0, 4.0 Hz), 3.14 (1H, dd,
was also produce compounds 7 and 8. Compounds 7 and 8 are J ¼ 11.0, 6.0 Hz). 13C-NMR (125 MHz, DMSO-d6): d 147.0, 145.3,
known compounds and they were identied by comparing their 134.3, 119.1, 114.7, 111.0, 75.9, 72.9, 62.6, 55.6; HRESIMS m/z
spectral data with those of the known compounds.29 Colorless 237.0733 [M
+
Na]+ (calcd for C10H14O5Na 237.0719).
oil; the specic rotations were [a]2D0 ꢀ14 (c 0.3 acetone) and Compounds 9 and 10 are known compounds and they were
[a]2D0 +15 (c 0.3 acetone), respectively. 1H-NMR (500 MHz, identied by comparing their spectral data with those of the
methanol-d4): d 8.23 (2H, d, J ¼ 8.5 Hz), 7.66 (2H, d, J ¼ 8.5 Hz), known compounds.7
4.74 (1H, d, J ¼ 7.0 Hz), 3.74 (1H, m), 3.68 (1H, dd, J ¼ 11.5, 4.5
4-((1S,2S)-1,2-Dihydroxy-3-(((1S,4R)-4,7,7-trimethyl-3-oxo-2-
Hz), 3.65 (1H, dd, J ¼ 11.5, 6.0 Hz). 1H-NMR (500 MHz, DMSO- oxabicyclo[2.2.1]heptane-1-carbonyl)oxy)propyl)-2-methox-
d6): d 8.17 (2H, d, J ¼ 8.5 Hz), 7.60 (2H, d, J ¼ 8.5 Hz), 4.72 (1H, d, yphenyl(1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]
J ¼ 5.5 Hz), 3.52 (1H, m), 3.42 (2H, overlap). 1H-NMR (500 MHz, heptane-1-carboxylate (10a). Compound 10 (3 mg, 0.014 mmol)
acetone-d6): d 8.19 (2H, d, J ¼ 8.5 Hz), 7.70 (2H, d, J ¼ 8.5 Hz), solution in dry CH2Cl2 or THF was added to a solution of
4.82 (1H, t, J ¼ 6.0 Hz), 3.75 (1H, m), 3.67 (1H, dd, J ¼ 11.0, 5.0 camphanic acid chloride (6 mg, 0.028 mmol), EDCI (5.3 mg,
Hz), 3.63 (1H, dd, J ¼ 11.0, 5.0 Hz). 13C-NMR (125 MHz, DMSO- 0.028 mmol) and DMAP (1.7 mg, 0.014 mmol) at 0 C with the
ꢂ
d6): d 151.8, 146.4, 128.5, 128.5, 122.6, 122.6, 75.2, 72.9, 62.9; protection of argon gas. The reaction was stirred at 0 ꢂC for 1 h
found 258.0619. HRESIMS m/z 258.0619 [M + HCOO]+ (calcd for and was detected by TLC. Then, the reaction was quenched by
C
10H12O7N 258.0620).
(2S,3R)-2,3-Dihydroxy-3-(4-nitrophenyl)propyl(1S,4R)-4,7,7-
dropwise addition of H2O. The suspension was extracted with
CH2Cl2. Removal of the solvent under reduced pressure and
trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate (7a). purication of the residue by preparative HPLC, eluting with
The synthesis procedure of 7a was same with the M1a. Colorless 55% methanol/H2O, gave the 10a 1.0 mg. Colorless oil; 1H-NMR
oil; 1H-NMR (500 MHz, methanol-d4): d 8.23 (2H, d, J ¼ 8.5 Hz), (500 MHz, methanol-d4): d 7.23 (1H, d, J ¼ 1.5 Hz), 7.08 (1H, d, J
7.66 (2H, d, J ¼ 8.5 Hz), 4.72 (1H, d, J ¼ 7.0 Hz), 4.46 (1H, dd, J ¼ ¼ 8.0 Hz), 7.02 (1H, dd, J ¼ 8.0, 1.5 Hz), 4.71 (1H, d, J ¼ 5.0 Hz),
11.5, 3.5 Hz), 4.35 (1H, dd, J ¼ 11.5, 6.5 Hz), 3.91 (1H, m), 2.50 4.34 (1H, dd, J ¼ 11.5, 4.0 Hz), 4.11 (1H, dd, J ¼ 11.5, 6.5 Hz),
(1H, m), 2.03 (1H, m), 1.98 (1H, m), 1.63 (1H, m), 1.11 (3H, s), 3.96 (1H, m), 3.86 (3H, s), 2.65 (1H, m), 2.49 (1H, m), 2.16 (2H,
1
1.09 (3H, s), 0.94 (3H, s). H-NMR (500 MHz, DMSO-d6): d 8.20 overlap), 2.02 (2H, overlap), 1.70 (1H, m), 1.63 (1H, m), 1.21 (3H,
(2H, d, J ¼ 9.0 Hz), 7.62 (2H, d, J ¼ 9.0 Hz), 4.58 (1H, dd, J ¼ 6.5, s), 1.14 (3H, s), 1.11 (3H, s), 1.09 (3H, s), 1.09 (3H, s), 0.94 (3H, s);
3.5 Hz), 4.39 (1H, dd, J ¼ 11.5, 3.0 Hz), 4.22 (1H, dd, J ¼ 11.5, 6.5 HRESIMS m/z 575.2487 [M + H]+ (calcd for C30H39O11 575.2490).
Hz), 3.73 (1H, m), 2.39 (1H, m), 1.98 (1H, m), 1.91 (1H, m), 1.55
Compound 11. White powder; 1H-NMR (500 MHz, DMSO-
(1H, m), 1.03 (3H, s), 1.00 (3H, s), 0.83 (3H, s). 13C-NMR (125 d6): d 6.88 (2H, overlap), 6.64 (2H, brs), 5.41 (2H, overlap), 4.56
MHz, methanol-d4): d 180.3, 168.9, 151.4, 148.8, 129.3, 129.3, (1H, d, J ¼ 6.0 Hz), 4.40 (1H, d, J ¼ 7.5 Hz), 3.77 (3H, s), 3.73 (6H,
124.1, 124.1, 92.9, 74.8, 74.0, 67.6, 56.0, 55.4, 31.5, 29.9, 17.0, s), 3.68 (2H, m), 3.64 (1H, m), 3.59 (1H, m), 3.46 (1H, m), 3.38
8114 | RSC Adv., 2021, 11, 8107–8116
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(2H, overlap), 3.17 (2H, overlap), 3.06 (3H, overlap). 13C-NMR
(125 MHz, methanol-d4): d 147.9, 147.9, 146.6, 142.9, 135.3,
133.5, 131.3, 128.7, 115.7, 112.2, 104.2, 103.7, 103.7, 87.3, 82.0,
76.9, 76.5, 75.2, 74.2, 70.0, 62.7, 61.9, 61.0, 56.0, 56.0, 55.7, 53.1;
HRESIMS m/z 607.2026 [M + Na]+ (calcd for C27H36O14Na
607.2000).
glycosides by 1H NMR spectroscopy, Org. Lett., 2016, 18,
4084.
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Conclusions
For natural AGs, there was previously no efficient method to
determine their absolute congurations. Our present study
presents a convenient and quick method for determining the
relative and absolute congurations that only depends on the
chemical shi difference (DdH3a–H3b) of the diastereotopic
methylene protons (H-3) in 1H NMR spectroscopy. In particular,
the method is a good way to determine the limited amounts of
natural AGs; such limited amounts prevent the use of other
8 H. Matsuura, H. Miyazaki, C. Asakawa, M. Amano,
T. Yoshihara and J. Mizutani, Isolation of a-glusosidase
inhibitors
from
hyssop
(Hyssopus
officinalis),
Phytochemistry, 2004, 65, 91.
9 S. Lin, S. J. Wang, M. T. Liu, M. L. Gan, S. Li, Y. C. Yang,
Y. H. Wang, W. Y. He and J. G. Shi, Glycosides from the
stem bark of Fraxinus sieboldiana, J. Nat. Prod., 2007, 70, 817.
strategies. Remarkably, the empirical rule is invalid in CDCl3. In 10 M. L. Gan, Y. L. Zhang, S. Lin, M. T. Liu, W. X. Song, J. C. Zi,
addition, the introduction of an economic camphanoyl group
with larger steric hindrance in this method may provide
a reference for solving the stereochemistry problems of other
exible conformer compounds.
Y. C. Yang, X. N. Fan, J. G. Shi, J. F. Hu, J. D. Sun and
N. H. Chen, Glycosides from the root of Iodes cirrhosa, J.
Nat. Prod., 2008, 71, 647.
11 X. Y. Chai, H. Y. Ren, Z. R. Xu, C. C. Bai, F. R. Zhou,
S. K. Ling, X. P. Pu, F. F. Li and P. F. Tu, Investigation of
two Flacourtiaceae plants: Bennettiodendron leprosipes and
Flacourtia ramontchi, Planta Med., 2009, 75, 1246.
12 L. Wang, F. Li, C. Y. Yang, A. A. Khan, X. Liu and M. K. Wang,
Neolignans, lignans and glycoside from the fruits of Melia
toosendan, Fitoterapia, 2014, 99, 92.
13 Y. L. Li, Y. X. Gao, H. Z. Jin, L. Shan, W. L. Chang, X. W. Yang,
H. W. Zeng, N. Wang, A. Steinmetz and W. D. Zhang,
Chemical constituents of Abies fabri, Phytochemistry, 2015,
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
This project was funded by the National Natural Science
Foundation of China (No. 81973194) and the Drug Innovation
Major Project (No. 2018ZX09711001-008). We appreciate Ms. Y.
H. Wang (Institute of Materia Medica, Chinese Academy of 14 X. X. Huang, M. Bai, L. Zhou, L. L. Lou, Q. B. Liu, Y. Zhang,
Medical Sciences and Peking Union Medical College) for testing
the NMR spectra.
L. Z. Li and S. J. Song, Food byproducts as a new and cheap
source of bioactive compounds: lignans with antioxidant
and anti-inammatory properties from Crataegus
pinnatida seeds, J. Agric. Food Chem., 2015, 63, 7252.
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