Divergent Synthesis of Natural Benzyl Salicylate and Benzyl Gentisate Glucosides

Article abstract of DOI:10.1021/acs.jnatprod.0c00838

Herein is reported the first total synthesis of benzyl salicylate and benzyl gentisate glucosides present in various plant species, in particular the Salix genus, such as Populus balsamifera and P. trichocarpa. The method permits the synthesis of several natural phenolic acid derivatives and their glucosides starting from salicylic or gentisic acid. The divergent approach afforded access to three different acetylated glucosides from a common synthetic intermediate. The key step in the total synthesis of naturally occurring glycosides - the selective deacetylation of the sugar moiety - was achieved in the presence of a labile benzyl ester group by employing mild deacetylation conditions. The protocol permitted synthesis of trichocarpine (4 steps, 40% overall yield), isotrichocarpine (3 steps, 51% overall yield), trichoside (6 steps, 40% overall yield), and deoxytrichocarpine (3 steps, 42% overall yield) for the first time (>95% purity). Also, the optimized mild deacetylation conditions allowed synthesis of 2-O-acetylated derivatives of all four glycosides (5-17% overall yield, 90-95% purity), which are rare plant metabolites.

Full text of DOI:10.1021/acs.jnatprod.0c00838

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Article
Divergent Synthesis of Natural Benzyl Salicylate and Benzyl
Gentisate Glucosides
Dariya D. Fedorova, Dariya S. Nazarova, David L. Avetyan, Andrey Shatskiy, Maxim L. Belyanin,
̈
̈
Markus D. Karkas, and Elena V. Stepanova*
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ABSTRACT: Herein is reported the first total synthesis of benzyl
salicylate and benzyl gentisate glucosides present in various plant
species, in particular the Salix genus, such as Populus balsamifera
and P. trichocarpa. The method permits the synthesis of several
natural phenolic acid derivatives and their glucosides starting from
salicylic or gentisic acid. The divergent approach afforded access to
three different acetylated glucosides from a common synthetic
intermediate. The key step in the total synthesis of naturally
occurring glycosidesthe selective deacetylation of the sugar
moietywas achieved in the presence of a labile benzyl ester
group by employing mild deacetylation conditions. The protocol
permitted synthesis of trichocarpine (4 steps, 40% overall yield),
isotrichocarpine (3 steps, 51% overall yield), trichoside (6 steps, 40% overall yield), and deoxytrichocarpine (3 steps, 42% overall
yield) for the first time (>95% purity). Also, the optimized mild deacetylation conditions allowed synthesis of 2-O-acetylated
derivatives of all four glycosides (5−17% overall yield, 90−95% purity), which are rare plant metabolites.
aturally occurring phenolic compounds and their
glycosides (also referred to as salicinoids or salicinoid
glycosylated form. The glucoside of benzyl gentisate
trichocarpine (5)was first isolated from P. trichocarpa19
and P. balsamifera20 along with its aglycone. However, in
subsequent reports only the presence of trichocarpine 5,21 2-O-
acetyl trichocartpine (6),22 and its isomer, isotrichocarpine
(7),23 with no free aglycone was demonstrated for various
plant species. Similarly, the analogous glucoside trichoside (8)
was isolated with no detectable free aglycone,24,25 indicating
that the free aglycone found in the early studies was likely
formed during the isolation process due to glucosidic bond
hydrolysis. Despite the abundance of benzyl salicylate (3) in
plants, the isolation of its glucoside 9 has been reported only
once, from Sarcandra glabra (Chloranthaceae).26 Finally,
salicylates and their glycosides can also be used for recognition
of certain plant species including morphologically similar
species or hybrids,27,28 as well as for understanding of
interactions of plants and insects with different levels of
specialization.29,30
N
phenolic glycosides) constitute a broad class of secondary
metabolites found in higher plants.1 A subclass of these
metabolites is derived from salicylic (1) and gentisic acids (2),
and their derivatives play the key role in plant defense2,3 and
regulate interactions between the plant and mammalian or
insect herbivores.4 Such compounds are particularly common
in plants of the willow family (Salicaceae) and can account for
up to 20 wt % of dry biomass.5 Besides the importance of these
phenolic compounds for regulation of biological functions in
plants, a variety have also been identified as active
pharmaceutical substances.6 Nevertheless, the total synthesis
of the related phenolic glycosides remains relatively unex-
plored.7
Benzyl salicylate (3) has been identified as one of the main
constituents of Walter’s dogwood (Cornus walteri)8 and other
plants, including Notopterygium incisium,9 Ocotea pulchella,10
Friesodielsia enghiana,11 and several species of the Aniba
genus.12 Benzyl salicylate (3) has been shown to display
significant nephroprotective8 and monoamine oxidase inhib-
itory effects,13 while it is also commonly used in the fragrance
industry14 and as an active component in sunscreens.15
Gentisic acid (2) and its esters have been found in numerous
plants16 and showed prominent wound healing and skin
lightening properties.17 Benzyl gentisate (4) and its glucoside
were isolated from Populus balsamifera,18 suggesting that such
phenolic esters are contained in plant tissues primarily in the
In the present work, we describe the total synthesis of four
phenolic glucosides, namely, trichocarpine (5), isotrichocar-
Received: July 28, 2020
© XXXX American Chemical Society and
American Society of Pharmacognosy
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Figure 1. Preparation of benzyl gentisates (4, 13, 14), benzyl salicylate (3), and their glucosides (5−9, 19−21).
pine (7), trichoside (8), and deoxytrichocarpine (9), as well as
their 2-O-acetyl derivatives 6, 19, 20, and 21, respectively, with
the respective aglycones obtained from the ubiquitous gentisic
and salicylic acids. Additionally, a divergent synthetic route to
an aglycone of trichoside (8) is discussed.
strategy, 2-methoxybenzoic acid (11) was converted to aryl
bromide 12 with molecular bromine in 83% yield, followed by
ipso-substitution of bromide 12 by a hydroxy group. The latter
reaction was carried out with the use of a common copper(II)
catalyst [Cu(OH)2-ethylenediamine] in water with the
addition of K2CO3 as a mild base, to afford 10 in satisfactory
yield (39%). The reaction provided a slightly lower yield when
the copper(II) catalyst was prepared in situ from CuSO4 and
ethylenediamine. Interestingly, the described optimized
procedure allowed avoiding conversion of the bromide 12 to
the respective aryl iodide, which was pivotal in the case of the
published procedures.37,38 Finally, benzylation of acid 10
furnished aglycone 14 in an excellent yield of 94%.
An alternative route for preparation of aglycone 14 starting
from gentisic acid (2) was also explored (Figure 1). In this
divergent route, aglycones 4 and 13 were also synthesized as
synthetic intermediates of aglycone 14. Gentisic acid was
benzylated to provide aglycone 4 (93% yield), which was
selectively acetylated with Ac2O to afford the monoacetyl
derivative 13. The initial attempts at pyridine-assisted
acetylation of 4 with a stoichiometric amount of Ac2O resulted
in isolation of a mixture of mono- and diacetylated products.
Fortunately, conducting the reaction in neat Ac2O in the
absence of pyridine allowed selective monoacetylation and
provided 13 in 83% yield. Under these conditions, it is likely
RESULTS AND DISCUSSION
■
One of the challenges in the total synthesis of glycosides of
salicylic acid derivatives is the synthesis of their relatively
simple aglycone moieties. The core part of the trichoside
aglycone 14 consists of 2-methoxy-5-hydroxybenzoic acid
(10). Synthesis of this acid has been described via multistep
procedures starting from gentisic acid (2) and using tosyl,31
benzyl,32 or tert-butyldimethylsilyl (TBS)33 protecting groups
(Figure 1). Several one-step procedures for preparation of acid
10 from 2-methoxybenzoic acid (11)34 or 4-methoxyphenol35
have been described; however, these procedures only gave the
target product with poor selectivity and low yield. Synthesis of
acid 10 via selective demethylation of fully methylated gentisic
acid was mentioned previously;36 however, our attempts at
reproducing this procedure resulted in isolation of only trace
amounts of the target product.
In this work, we devised an alternative strategy for the
synthesis of acid 10 needed for accessing aglycone 14. In this
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that the regioselectivity of the reaction relies on the steric
hindrance exerted by the carboxybenzyl group in phenol 4.
Introduction of the acetyl group at C-1 in 13 was confirmed by
HMBC experiments (Figure 1, see the Supporting Informa-
tion), which demonstrated correlation between the CH3
protons of the acetyl group and C-1 (δH 2.30/δC 142.5) and
between the OH proton and C-4 (δH 10.70/δC 159.5). Acetate
13 was converted to aglycone 14 via sequential methylation
and deacetylation reactions. Despite the presence of two ester
groups in methylated 13, selective deacetylation was achieved
in good yield when conducting the reaction under mild acidic
conditions (HCl in EtOH/CHCl3).7f No trace of the
debenzylated product was detected during deacetylation,
providing trichoside aglycone 14 in 80% yield over two steps.
The phenolic glucosides were then synthesized with phenols
4, 13, and 14 as glucosyl acceptors, affording tetraacetate
glucosides isotrichocarpine (15), trichocarpine (16), and
trichoside (17), respectively. Isotrichocarpine tetraacetate
(15) was prepared in one step from benzyl gentisate (4),
using penta-O-acetyl-β-D-glucose as the glucosyl donor. In this
reaction, the steric hindrance exerted by the carboxybenzyl
group permitted selective formation of only one product with
no traces of the isomeric glucoside or diglucoside. Surprisingly,
the same glucosylation method (β-D-glucose pentaacetate,
promoted by BF3·Et2O)39 did not result in formation of any
product in the case of phenols 13, 14, and 3. Presumably, for
these aglycones strong coordination of the Lewis acid between
the ortho-positioned phenolic and ester groups prevents
nucleophilic attack on the reactive species generated from
the glucosyl donor. Gratifyingly, glucosylation of 13, 14, and 3
was achieved successfully under Koenigs−Knorr conditions,40
providing the target glucosides 16, 17, and 18 in high yields
(70%, 78%, and 80%, respectively).
The final step in the total synthesis of the glucosylated
salicylic acid derivatives comprises selective deacetylation of
tetraacetate precursors 15−18. Herein, chemoselective deace-
tylation plays a crucial role, sine the precursors 15−18 contain
both acetyl ester groups in the sugar moiety and a benzyl ester
group in the aglycone moiety. The typical procedures for
deacetylation, such as the Zemplen procedure (sodium
methoxide in methanol)41,42 or other base-catalyzed deacety-
lation procedures,43 proved nonselective for removal of the
acetyl ester groups. Therefore, an alternative procedure that
was recently applied by our group for selective removal of
acetyl groups in the presence of other ester groups for a
number of phenolic glycosides was employed.7d−f Selective
deacetylation of tetraacetates 15, 16, 17, and 18 was thereby
achieved through mild acidic ethanolysis and afforded the
target naturally occurring glucosides isotrichocarpine (7),
trichocarpine (5), trichoside (8), and deoxytrichocarpine (9),
respectively, in good yields (78%, 74%, 69%, and 53%). This is
the first demonstration of the total synthesis of these natural
compounds. Along with glucosides 5, 7, 8, and 9, their 2-O-
acetyl derivatives 6, 19, 20, and 21, respectively, could also be
obtained by carefully controlling the reaction time. Owing to
the higher hydrolytic stability of 2-O-acetyl groups in phenyl
glucosides,44,45 selective deacetylation of tetra-O-acetyl gluco-
sides under reduced reaction times furnished the 2-O-acetyl
derivatives 6, 19, 20, and 21, albeit in moderate yields (9%,
22%, 30%, and 13%).
three glucosides, namely, trichocarpine, isotrichocarpine, and
trichoside, along with their 2-O-acetyl derivatives were
obtained using benzyl gentisate as a common synthetic
intermediate. The preparation of the core trichoside aglycone,
2-methoxy-5-hydroxybenzoic acid, was improved by reducing
the number of synthetic steps from four or five in the
previously reported procedures to two in the current approach.
Selective HCl-catalyzed deacetylation permitted preparation of
deprotected glycosides in high yields (74% for trichocarpine,
78% for isotrichocarpine, 69% for trichoside, and 53% for
deoxytrichocarpine) and their 2-O-acetyl derivatives in modest
yields (9% for 2-O-acetyltrichocarpine, 22% for 2-O-acetyl-
isotrichocarpine, 30% for 2-O-acetyltrichoside, and 13% for 2-
O-acetyldeoxytrichocarpine). The purity of all products was
1
estimated from H NMR spectra and exceeded 95% for fully
deprotected glycosides and 90−95% for 2-O-acetylglucosides.
EXPERIMENTAL SECTION
■
General Experimental Procedures. The reactions were
performed with commercial reagents purchased from Merck,
Darmstadt, Germany, or Acros Organics (Thermo Fisher Scientific),
Geel, Belgium. Anhydrous solvents were purified and dried according
to standard procedures. Uncorrected melting points were determined
using an MP50 melting point system (Mettler Toledo). UV spectra
were recorded using EtOH solutions (ca. 0.005 wt %) with an
Evolution 600 UV−visible spectrophotometer. Optical rotations were
measured on a POP-1/2 automatic compact polarimeter. IR spectra
were recorded on neat samples using an Agilent Cary 630 FTIR
spectrometer with attenuated total reflectance (ATR). H and 13C
1
NMR spectra were acquired for solutions in CDCl3, DMSO-d6, or
methanol-d4 on a Bruker AVANCE III HD instrument (400 and 101
MHz for 1H and 13C, respectively). The 1H NMR chemical shifts are
referenced to the residual signal of CHCl3 (δH 7.26), DMSO-d5 (δH
2.50), methanol-d3 (δH 3.31), acetone-d5 (δH 2.05), or HDO (δH
4.79), and the 13C NMR shifts are referenced to the central line of the
CDCl3 signal (δC 77.00), DMSO-d6 (δC 39.52), acetone-d6 (δC
29.84), and methanol-d4 (δC 49.00). Assignment of the signals in
the NMR spectra was performed using 2D-NMR experiments
(COSY, HSQC, and HMBC). The purity of the synthesized
compounds was estimated from 1H NMR spectra. HR-ESIMS spectra
were recorded in positive ion mode on a Bruker micrOTOF II mass
spectrometer for 2 × 10−5 M solutions in MeCN. Column
chromatography was performed on silica gel 60 (40−63 μm, Merck,
Darmstadt, Germany). Flash chromatography was carried out on a
Reveleris X2 Buchi chromatograph using FlashPure Select C18 30 μm
̈
columns. TLC was carried out on silica gel 60 F254 plates on
aluminum foil (Merck, Darmstadt, Germany). The eluent systems
used for chromatographic purification and TLC are specified for each
compound in their respective synthetic procedures. TLC spots were
visualized under UV light (254 nm) or by heating the TLC plates to
ca. 300 °C after immersion in a 1:10 (v/v) mixture of 85% aqueous
H3PO4 and MeOH (for glucosides) or in a 2% solution of FeCl3 in
water (for aglycones).
5-Bromo-2-methoxybenzoic acid (12). 2-Methoxybenzoic acid 11
(7.6 g, 50 mmol) was dissolved in glacial HOAc (25 mL), and a
solution of Br2 (3.88 mL, 75 mmol) in HOAc (25 mL) was added
dropwise over 1 h. The reaction mixture was stirred at room
temperature (∼20 °C) for 2 h, ice-cold water (150 mL) was added,
stirring was continued for 30 min, and the precipitate was filtered and
extensively washed with water. The precipitate was recrystallized from
EtOH and air-dried to give the title compound as white needles (9.7
g, 84%, purity >95%): Rf = 0.37 (hexanes/EtOAc, 7:2); mp 116−117
°C (lit. 120−122 °C);46 UV (EtOH) λmax 231, 306 nm; ATR-FTIR
νmax 3070−2200 (br) 1699, 1666, 1485, 1232, 1012, 812, 674 cm−1;
1H NMR (400 MHz, CDCl3, δ, ppm, J, Hz) 4.07 (s, 3H, OMe), 6.96
(d, 1H, J 8.7, H-5), 7.67 (dd, 1H, J 2.6, J 8.7, H-6), 8.29 (s, 1H, H-2);
13C NMR (101 MHz, CDCl3, δ, ppm) 57.0, 113.5, 114.7, 119.3,
In conclusion, efficient procedures for the preparative
synthesis of several natural glucosides of salicylic and gentisic
acid benzyl esters were developed. Using a divergent approach
C
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136.2, 137.6, 157.1, 164.1. The spectroscopic data are in agreement
with literature data.46
in vacuo, the residue was dissolved in CH2Cl2 (50 mL) and washed
with 1 M NaOH (2 × 50 mL) and water (2 × 50 mL), and the
aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The
combined organic extract was dried over Na2SO4 and filtered, and the
solids were washed with CH2Cl2 (4 × 10 mL). The combined filtrate
was concentrated under reduced pressure and dried in vacuo. The
residue was purified by silica gel column chromatography (toluene →
toluene/EtOAc, 9:1) to give the methylated compound as a colorless
oil: Rf = 0.49 (toluene/EtOAc, 45:1); HR-ESIMS m/z 323.0891
(calcd for C17H16O5Na, 323.0890). The residue was dissolved in a
mixture of EtOH and CHCl3 (35 mL, 1.8:1 v/v), and concentrated
HCl (4.5 mL) was added. The reaction mixture was stirred at room
temperature (∼20 °C) for 7 h, solvents were evaporated in vacuo, the
residue was dissolved in toluene (50 mL) and washed with saturated
aqueous NaHCO3 (2 × 50 mL), and the aqueous layer was extracted
with toluene (2 × 30 mL). The combined organic extract was dried
over Na2SO4 and filtered, and the solids were washed with toluene (4
× 10 mL). The combined filtrate was concentrated under reduced
pressure, and the residue was purified by silica gel column
chromatography (toluene → toluene/EtOAc, 75:25) to give 4.12 g
(80% over 2 steps, purity 94%) of the title compound as a white solid:
Rf = 0.28 (toluene/EtOAc, 45:1); mp 60−62 °C; UV (EtOH) λmax
238, 325 nm; ATR-FTIR νmax 3372, 2843, 1735, 1575, 1487, 1200,
1027, 784 cm−1; 1H NMR (400 MHz, CDCl3, δ, ppm, J, Hz) 3.81 (s,
3H, OMe), 5.31 (s, 2H, CH2), 6.84 (d, 1H, J 8.9, H-5), 6.98 (dd, 1H,
J 3.0, J 8.9, H-6), 7.26−7.42 (m, 6H, H-2, C6H5); 13C NMR (101
MHz, CDCl3, δ, ppm) 56.6 (OMe), 66.7 (CH2), 113.8 (C-5), 118.1
(C-2), 119.9 (C-3), 120.8 (C-6), 128.1 (CH, C6H5), 128.1 (2 × CH,
C6H5), 128.5 (2 × CH, C6H5), 135.9 (C, C6H5), 149.1 (C-1), 153.6
(C-4), 165.9 (CO); HR-ESIMS m/z 281.0785 (calcd for
C15H14O4Na, 281.0784). The spectroscopic data are in agreement
with the anticipated structure.
5-Hydroxy-2-methoxybenzoic acid (10). Bromide 12 (0.3 g, 1.3
mmol) and K2CO3 (0.27 g, 1.9 mmol) were dissolved in water (12
mL) under sonication, followed by addition of a 1 M aqueous solution
of [Cu(OH)2(EDA)2] (0.32 mL, 0.32 mmol, 25 mol %) and purging
of the reaction mixture with nitrogen for 10 min. The reaction
mixture was heated at 100 °C for 6 h under nitrogen, after which it
was cooled and the pH of the mixture was adjusted to 4 with 0.1 M
aqueous HCl. The mixture was extracted with EtOAc (4 × 20 mL),
and the combined organic extract was dried over Na2SO4, filtered, and
concentrated, resulting in a crude product as a yellow solid. The crude
product was purified by silica gel column chromatography (toluene/
acetone, 6:1, → toluene/acetone, 1:1, 0.05% (v/v) HOAc) to give the
product as an off-white solid: 86 mg (39%), purity >95%; Rf = 0.30
(hexanes/EtOAc, 7:2); mp 155−156 °C (lit. 171−173 °C from
EtOAc);31 UV (EtOH) λmax 232, 320 nm; ATR-FTIR νmax 3426 (br),
2920, 2851, 1667, 1584, 1490, 1261, 1206, 1180, 890, 814, 749, 676
1
cm−1; H NMR (400 MHz, acetone-d6, δ, ppm, J, Hz) 3.99 (s, 3H,
OMe), 7.06 (dd, 1H, J 3.0, J 8.9, H-6), 7.11 (d, 1H, J 8.9, H-5), 7.43
(d, 1H, J 3.0, H-2), 8.35 (s, 1H, OH), 10.98 (s, 1H, OH); 13C NMR
(101 MHz, acetone-d6, δ, ppm) 57.5, 115.0, 118.8, 120.4, 121.9,
152.3, 152.9, 165.9. The spectroscopic data are in agreement with the
literature.31
Benzyl 2,5-dihydroxybenzoate (benzyl gentisate) (4): Gentisic
acid 2 (7.86 g, 51 mmol) and NaHCO3 (22 g, 260 mmol) were
dissolved in dry DMF (50 mL), the mixture was stirred for 5 min, and
BnBr (6 mL, 51 mmol) was added. The reaction mixture was stirred
at room temperature (∼20 °C) for 18 h, ice-cold water (200 mL) was
added, and stirring was continued for 30 min, after which the
precipitate was filtered and extensively washed with water. The
precipitate was transferred to a beaker, and boiling toluene (100 mL)
was added. After the complete dissolution of all solids the upper
toluene layer was accurately transferred to dry a beaker and slowly
cooled to −20 °C. The precipitate was filtered, washed with cold
toluene (2 × 30 mL), and air-dried to give the title compound as
white needles (11.57 g, 93%, purity >95%): Rf = 0.48 (toluene/EtOH,
9:1); mp 102−103 °C (lit. 104.5 °C,18 102−103 °C47); UV (EtOH)
λmax 230, 290 nm; ATR-FTIR νmax 3227 (br), 2940, 2873, 1654, 1616,
Benzyl 5-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-2-
hydroxybenzoate (isotrichocarpine tetraacetate) (15). Benzyl
gentisate (4) (1.013 g, 4.15 mmol) and the pentaaceate of β-D-
glucose A (2.56 g, 6.57 mmol) were dissolved in dry CH2Cl2 (30 mL)
under nitrogen, and Et3N (0.460 mL, 3.3 mmol) was added, followed
by BF3·Et2O (1.96 mL, 16.4 mmol). The reaction mixture was stirred
at room temperature (∼20 °C) for 18 h, saturated NaHCO3 (50 mL)
was added, the organic layer was separated, the aqueous layer was
extracted with CH2Cl2 (3 × 50 mL), the combined organic extract
was dried over Na2SO4, filtered, concentrated under reduced pressure,
and the residue was recrystallized from hot EtOH to give the title
compound as white crystals (1.66 g, 70%, purity >95%): Rf = 0.44
(PhMe/EtOH, 18:1); mp 105−106 °C; [α]26D −5.9 (c 0.49, CHCl3);
UV (EtOH) λmax 238, 324 nm; ATR-FTIR νmax 3142, 2972, 1750,
1
1483, 1194, 1071, 779, 695 cm−1; H NMR (400 MHz, CDCl3, δ,
ppm, J, Hz) 5.35 (s, 2H, CH2), 6.88 (d, 1H, J 8.9, H-5), 7.00 (dd, 1H,
J 3.0, J 8.9, H-6), 7.32 (d, 1H, J 3.0, H-2), 7.36−7.41 (m, 5H, C6H5),
10.39 (s, 1H, OH); 13C NMR (101 MHz, CDCl3, δ, ppm) 67.1
(CH2), 112.1, 114.8, 118.5, 124.2, 128.2 (2 × CH), 128.6, 128.7 (2 ×
CH), 135.1, 147.7, 155.7, 169.5. The spectroscopic data are in
agreement with the literature data.18,48
1
1677, 1485, 1202, 1038, 836, 788, 701 cm−1; H NMR (400 MHz,
Benzyl 5-acetoxy-2-hydroxybenzoate (13). Phenol 4 (4.88 g, 20
mmol) was dissolved in Ac2O (6.8 mL, 72 mmol). The reaction
mixture was stirred at room temperature (∼20 °C) for 24 h, the
solvent was evaporated in vacuo, and the residue was purified by silica
gel column chromatography (toluene → toluene/EtOAc, 7:1) to give
the title compound as a white solid (4.75 g, 83%, purity >95%): Rf =
0.88 (toluene/EtOAc, 20:1); mp 55−56 °C; UV (EtOH) λmax 237,
314 nm; ATR-FTIR νmax 3201 (br), 3073, 1758, 1671, 1485, 1204,
CDCl3, δ, ppm, J, Hz) 2.02, 2.03, 2.03, 2.03 (s, 4 × 3H, Ac), 3.76
(ddd, 1H, J 2.0, J 4.6, J 9.8, H-5Glc), 4.06 (dd, 1H, J 2.0, J 12.3, H-
6aGlc), 4.27 (dd, 1H, J 4.6, J 12.3, H-6bGlc), 4.94 (d, 1H, J 7.4, H-1Glc),
5.16 (dd∼t, 1H, J 9.5, H-4Glc), 5.19−5.29 (m, 2H, H-2Glc, H-3Glc),
5.37 (s, 2H, CH2), 6.91 (d, 1H, J 9.0, H-5), 7.16 (dd, 1H, J 2.9, J 9.0,
H-6), 4.37−7.44 (m, 5H, C6H5), 7.47 (d, 1H, J 2.9, H-2), 10.48 (s,
1H, OH); 13C NMR (101 MHz, CDCl3, δ, ppm) 20.56, 20.59, 20.61
(4 × CH3, Ac), 61.6 (C-6), 67.2 (CH2), 68.0 (C-4Glc), 71.1 (C-2Glc or
C-3Glc), 72.0 (C-5Glc), 72.6 (C-2Glc or C-3Glc), 100.3 (C-1Glc), 112.2
(C-3), 118.2 (C-2), 118.5 (C-5), 126.5 (C-6), 128.3 (2 × CH, C6H5),
128.7 (CH, C6H5), 128.7 (2 × CH, C6H5), 135.0 (C, C6H5), 148.9
(C-4), 158.0 (C-1), 169.2, 169.3, 169.3, 170.2, 170.5 (CO); HR-
ESIMS m/z 597.1577 (calcd for C28H30O13Na, 597.1579). The
spectroscopic data are in agreement with the anticipated structure.
General Procedure for Ag2O-Promoted Glycosylation. α-
Bromotetra-O-acetylglucose (B) (1 equiv) and phenol 3, 13, or 14
(1.05 equiv) were dissolved in quinoline (1 mL per 1 g of α-
bromotetra-O-acetylglucose), and ground Ag2O (1.05 equiv) was
added. The reaction mixture was stirred using a glass spatula upon
thickening at room temperature (∼20 °C) for 1 h, followed by
addition of CHCl3 (30 mL). The reaction mixture was centrifuged,
the supernatant was combined, and the solids were carefully washed
with CHCl3 (3 × 10 mL). The combined organic phases were washed
1
743, 681 cm−1; H NMR (400 MHz, CDCl3, δ, ppm, J, Hz) 2.27 (s,
3H, CH3, Ac), 5.37 (s, 2H, CH2), 6.99 (d, 1H, J 9.0, H-5), 7.19 (dd,
1H, J 2.9, J 9.0, H-6), 7.37−7.45 (m, 5H, C6H5), 7.57 (d, 1H, J 2.9,
H-2), 10.68 (s, 1H, OH); 13C NMR (101 MHz, CDCl3, δ, ppm) 20.9
(CH3, Ac), 67.3 (CH2), 112.3 (C-3), 118.4 (C-5), 122.1 (C-2), 128.4
(2 × CH, C6H5), 128.6 (2 × CH, C6H5), 128.7 (CH, C6H5), 129.5
(C-6), 134.9 (C, C6H5), 142.3 (C-1), 159.4 (C-4), 169.2 (CO), 169.7
(CO, Ac). The spectroscopic data are in agreement with the
anticipated structure.
Benzyl 5-hydroxy-2-methoxybenzoate (14). From acid 10:
Benzylation of 10 (100 mg, 0.6 mmol) was carried out under the
same conditions as for 4; yield of 14, 145 mg (94%). From phenol 13:
Monoacetate 13 (5.7 g, 20 mmol) was dissolved in dry acetone (100
mL), K2CO3 (15 g, 108 mmol) and MeI (1.37 mL, 22 mmol) were
added, and the mixture was refluxed for 4 h until complete
consumption of the starting material. The acetone was evaporated
D
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J. Nat. Prod. XXXX, XXX, XXX−XXX

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Article
with 1 M KOH (4 × 50 mL) and 5% aqueous H2SO4 (4 × 50 mL),
dried over Na2SO4, filtered through a glass filter filled with SiO2 to
remove residual silver salts, washed with CHCl3 (150 mL), and
concentrated under reduced pressure, and the residue was recrystal-
lized from hot EtOH.
Benzyl 2-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-
acetoxybenzoate (trichocarpine pentaacetate) (16). 16 was
prepared following the general procedure from phenol 13 (0.45 g,
1.6 mmol) and isolated as white crystals (0.69 mg, 70%, purity
>95%): Rf = 0.83 (toluene/EtOH, 9:1); mp 113−114 °C (lit 117−
118 °C);48 [α]26D −17.9 (c 0.39, CHCl3); UV (EtOH) λmax 230, 290
nm; ATR-FTIR νmax 2943, 1731, 1493, 1207, 1032, 751, 696 cm−1;
1H NMR (400 MHz, CDCl3, δ, ppm, J, Hz) 2.03, 2.04, 2.04, 2.06,
2.28 (s, 5 × CH3, Ac), 3.81 (ddd, 1H, J 2.0, J 5.2, J 9.2, H-5Glc), 4.15
(dd, 1H, J 2.0, J 12.2, H-6aGlc), 4.26 (dd, 1H, J 5.2, J 12.2, H-6bGlc),
5.06 (d, 1H, J 7.2, H-1Glc), 5.15 (dd∼t, 1H, J 9.2, H-4Glc), 5.24−5.33
(m, 4H, CH2, H-2Glc, H-3Glc), 7.15−7.20 (m, 2H, H-6, H-5), 7.31−
7.42 (m, 5H, C6H5), 7.48−7.49 (m, 1H, H-2); 13C NMR (101 MHz,
CDCl3, δ, ppm) 20.57, 20.58, 20.7, 20.9 (5 × CH3, Ac), 61.8 (C-6Glc),
66.8 (CH2), 68.2 (C-4Glc), 70.7 (C-2Glc), 72.0 (C-5Glc), 72.6 (C-3Glc),
100.0 (C-1Glc), 119.2 (C-5), 123.4 (C-3), 124.1 (C-2), 126.3 (C-6),
128.2 (CH, C6H5), 128.3 (2 × CH, C6H5), 128.5 (2 × CH, C6H5),
135.8 (C, C6H5), 145.7 (C-1), 153.4 (C-4), 164.0 (CO), 169.3,
169.4, 169.4, 170.2, 170.5 (5 × CO, Ac); HR-ESIMS m/z 639.1680
(calcd for C30H32O14Na, 639.1684). The spectroscopic data are in
agreement with the anticipated structure.
of CHCl3 (1.2 mL) and EtOH (3 mL), and concentrated HCl (1 mL)
was added. The reaction mixture was stirred at room temperature
(∼20 °C) for 10−22 h and concentrated under reduced pressure (the
bath temperature should not exceed 40 °C and distillation time
should not exceed 20 min). The residue was purified by silica gel
column chromatography (CHCl3/EtOH, 90:10 → 50:50) to give
both deacetylated compound and the 2-O-acetyl derivative. The
reaction time determines the yield of each.
Benzyl 2-(β-D-glucopyranosyloxy)-5-hydroxybenzoate (tricho-
carpine) (5). 5 was obtained following the general procedure from
pentaacetate 16 (207 mg, 0.34 mmol) with 16 h of reaction time and
additionally recrystallized from EtOH to give 100 mg (74%, purity
>95%) of colorless crystals: Rf = 0.45 (CHCl3/EtOH, 5:1); mp 134−
136 °C (lit. 134−136 °C);22 [α]26 −19.8 (c 0.50, EtOH); UV
D
(EtOH) λmax 238, 312 nm; ATR-FTIR νmax 3408 (br), 2921, 2851,
1701, 1496, 1201, 1065, 695 cm−1; 1H NMR (400 MHz, methanol-d4,
δ, ppm, J, Hz) 3.35−3.41 (m, 2H, H-4Glc, H-5Glc), 3.42−3.49 (m, 2H,
H-2Glc, H-3Glc), 3.69 (dd, 1H, J 5.4, J 12.1, H-6aGlc), 3.90 (dd, 1H, J
1.8, J 12.1, H-6bGlc), 4.72 (m, 1H, H-1Glc), 5.33 (ABq∼q, 2H, J 12.4,
CH2), 6.96 (dd, 1H, J 3.1, J 8.9, H-6), 7.19 (d, 1H, J 3.1, H-2), 7.28
(d, 1H, J 8.9, H-5), 7.39 (m, 5H, C6H5); 13C NMR (101 MHz,
methanol-d4, δ, ppm) 62.6 (C-6Glc), 68.1 (CH2), 71.3 (C-4Glc), 75.0
(C-2Glc or C-3Glc), 77.5 (C-2Glc or C-3Glc), 78.4 (C-5Glc), 105.3 (C-
1Glc), 117.6 (C-2), 121.5 (C-5), 121.9 (C-6), 123.2 (C-3), 129.3 (2 ×
CH, C6H5), 129.4 (CH, C6H5), 129.6 (2 × CH, C6H5), 137.4 (C,
C6H5), 151.9 (C-1), 154.1 (C-4), 167.8 (CO); HR-ESIMS m/z
429.1145 (calcd for C20H22O9Na, 429.1156). The spectroscopic data
are in agreement with the literature.22,49
Benzyl 2-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-
acetoxybenzoate (trichoside tetraacetate) (17). 17 was prepared
following the general procedure from phenol 14 (1.0 g, 3.9 mmol)
and isolated as white crystals (1.69 g, 78%, purity >95%): Rf = 0.52
Benzyl 2-(2-O-acetyl-β-D-glucopyranosyloxy)-5-hydroxyben-
zoate (2-O-acetyltrichocarpine) (6). 6 was obtained following the
general procedure from pentaacetate 16 (207 mg, 0.34 mmol) with 10
h of reaction time to give 14 mg (9%, purity 90%) of a white,
(toluene/EtOH, 9:1); mp 103−105 °C (lit. 116−118 °C);24 [α]26
D
−10.3 (c 0.60, CHCl3); UV (EtOH) λmax 209, 237, 308 nm; ATR-
FTIR νmax 2968, 1751, 1733, 1498, 1375, 1206, 1069, 1039, 825, 746,
amorphous powder: Rf = 0.50 (CHCl3/EtOH, 5:1); [α]26 −17.6 (c
D
1
699 cm−1; H NMR (400 MHz, CDCl3, δ, ppm, J, Hz) 2.02, 2.03,
0.50, EtOH); UV (EtOH) λmax 232, 308 nm; ATR-FTIR νmax 3442
(br), 2924, 2863, 1720, 1496, 1200, 1066, 1027, 697 cm−1; 1H NMR
(400 MHz, methanol-d4, δ, ppm, J, Hz) 2.08 (s, 3H, CH3, Ac), 3.43−
3.47 (m, 2H, H-3Glc, H-5Glc), 3.58 (dd∼t, 1H, J 9.1, H-4Glc), 3.70 (dd,
1H, J 5.1, J 12.1, H-6aGlc), 3.90 (d, 1H, J 12.1, H-6bGlc), 4.93 (d, 1H, J
8.1, H-1Glc), 5.00 (dd, 1H, J 8.1, J 9.2, H-2Glc), 5.25, 5.32 (ABq, 2H, J
12.4, CH2), 6.90 (dd, 1H, J 3.1, J 9.0, H-6), 7.04 (d, 1H, J 3.1, H-2),
7.18 (d, 1H, J 9.0, H-5), 7.36 (m, 5H, C6H5); 13C NMR (101 MHz,
methanol-d4, δ, ppm) 19.8 (CH3, Ac), 61.1 (C-6Glc), 66.4 (CH2), 69.9
(C-4Glc), 73.4 (C-2Glc), 74.7 (C-3Glc), 76.9 (C-5Glc), 100.5 (C-1Glc),
115.7 (C-5), 118.8 (C-3), 119.4 (C-2), 123.0 (C-6), 127.8 (CH,
C6H5), 127.9 (2 × CH, C6H5), 128.2 (2 × CH, C6H5), 136.3 (C,
C6H5), 149.0 (C-1), 152.4 (C-4), 166.1 (CO), 170.6 (CO, Ac). The
spectroscopic data are in agreement with the literature.22
2.04, 2.04 (s, 4 × CH3, Ac), 3.78 (ddd, 1H, J 2.3, J 5.0, J 9.9, H-5Glc),
3.86 (s, 3H, OMe), 4.08 (dd, 1H, J 2.3, J 12.3, H-6aGlc), 4.26 (dd, 1H,
J 5.0, J 12.3, H-6bGlc), 4.97 (d, 1H, J 7.5, H-1Glc), 5.15 (dd∼t, 1H, J
9.5, H-4Glc), 5.24 (m, 2H, H-2Glc, H-3Glc), 5.33 (s, 2H, CH2), 6.90 (d,
1H, J 9.1, H-5), 7.13 (dd, 1H, J 3.1, J 9.0, H-6), 7.32−7.45 (m, 5H,
C6H5), 7.47 (d, 1H, J 3.1, H-2); 13C NMR (101 MHz, CDCl3, δ,
ppm) 20.55, 20.57, 20.59, 20.61 (4 × CH3, Ac), 56.5 (OMe), 61.7
(C-6Glc), 66.7 (CH2), 68.0 (C-4Glc), 71.1 (C-2Glc or C-3Glc), 72.0 (C-
5Glc), 72.6 (C-2Glc or C-3Glc), 100.0 (C-1Glc), 113.3 (C-5), 120.4 (C-
3), 120.5 (C-6), 123.2 (C-5), 128.0 (2 × CH, C6H6), 128.2 (CH,
C6H6), 128.5 (2 × CH, C6H6), 135.9 (C, C6H6), 149.9 (C-4), 155.6
(C-1), 165.2 (CO), 169.3, 169.3, 170.2, 170.6 (4 × CO, Ac); HR-
ESIMS m/z 611.1737 (calcd for C29H32O13Na, 611.1735). The
spectroscopic data are in agreement with the anticipated structure.
Benzyl 2-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-
benzoate (deoxytrichocarpine tetraacetate) (18). 18 was prepared
following the general procedure from phenol 3 (1.0 g, 4.4 mmol) as
white crystals (1.87 g, 80%, purity >95%): Rf = 0.54 (hexanes/EtOAc,
Benzyl 5-(β-D-glucopyranosyloxy)-2-hydroxybenzoate (isotricho-
carpine) (7). 7 was obtained following the general procedure from
tetraacetate 15 (246 mg, 0.43 mmol) with 22 h of reaction time and
additionally recrystallized from EtOH to give 136 mg (78%, purity
>95%) of colorless crystals: Rf = 0.21 (CHCl3/EtOH, 10:1); mp
1:1); mp 107−108 °C; [α]26 − 74.2 (c 0.59, CHCl3); UV (EtOH)
D
124−125 °C; [α]28 −36.8 (c 0.50, EtOH); UV (EtOH) λmax 240,
D
λmax 227, 284 nm. ATR-FTIR νmax 2967, 1753, 1730, 1374, 1223,
1
1038, 761 cm−1; H NMR (400 MHz, CDCl3, δ, ppm, J, Hz) 2.04,
331 nm; ATR-FTIR νmax 3514 (br), 3379 (br), 3045, 2927, 2868,
1
1686, 1616, 1488, 1201, 1072, 1015, 730, 691 cm−1; H NMR (400
2.05 (s, 4 × CH3, Ac), 3.85 (ddd, 1H, J 2.2, J 4.8, J 7.0, H-5Glc), 4.17
(d, 1H, J 12.2, H-6aGlc), 4.27 (d, 1H, J 12.2, H-6bGlc), 5.10 (d, 1H, J
MHz, DMSO-d6, δ, ppm, J, Hz) 3.13−3.26 (m, 4H, H-2Glc, H-3Glc, H-
4Glc, H-5Glc), 3.47 (ddd∼dt, 1H, J 5.7, J 11.6, H-6aGlc), 3.63 (dd, 1H, J
4.8, J 10.8, H-6bGlc), 4.58 (dd∼t, 1H, J 5.7, OH-6Glc), 4.69 (d, 1H, J
7.4, H-1Glc), 5.03 (d, 1H, J 5.0, OHGlc), 5.10 (d, 1H, J 4.4,OH Glc),
5.33 (d, 1H, J 4.7, OHGlc), 5.36, 5.40 (ABq, 2H, J 12.6, CH2), 6.94 (d,
1H, J 9.0, H-5), 7.28 (dd, 1H, J 3.0, J 9.0, H-6), 7.35−7.50 (m, 6H, H-
2, C6H5), 10.15 (s, 1H, OH); 13C NMR (101 MHz, DMSO-d6, δ,
ppm) 60.5 (C-6Glc), 66.6 (CH2), 69.5 (C-4Glc), 73.2 (C-2Glc), 76.5
(C-3Glc), 77.1 (C-5Glc), 101.9 (C-1Glc), 113.0 (C-3), 117.0 (C-2),
118.3 (C-5), 125.2 (C-6), 128.1 (2 × CH, C6H5), 128.3 (CH, C6H5),
128.6 (2 × CH, C6H5), 135.7 (C, C6H5), 149.9 (C-4), 155.3 (C-1),
168.1 (CO); HR-ESIMS m/z 429.1145 (calcd for C20H22O9Na,
429.1156). The spectroscopic data are in agreement with the
literature.23
6.8, H-1), 5.16 (dd∼t, 1H, J 9.2, H-4Glc), 5.26−5.35 (m, 4H, H-2Glc
,
H-3Glc, CH2), 7.11−7.17 (m, 2H, CH, Ar), 7.26−7.44 (m, 6H, C6H5,
CH, Ar), 7.75 (d, 1H, J 7.5, CH, Ar); 13C NMR (101 MHz, CDCl3, δ,
ppm) 20.6, 20.6, 20.6 (4 × CH3, Ac), 61.9 (C-6Glc), 66.6 (CH2), 68.2
(C-4Glc), 70.7 (C-2Glc or C-3Glc), 72.0 (C-5Glc), 72.6 (C-2Glc or C-
3Glcl), 99.7 (C-1Glc), 117.5 (CH, Ar), 122.6 (C-2), 123.2 (CH, Ar),
128.1 (CH, C6H5), 128.2 (2 × CH, C6H5), 128.5 (2 × CH, C6H5),
131.1 (CH, Ar), 133.0 (CH, Ar), 136.0 (C, C6H5), 155.7 (C-1), 165.3
(CO), 169.4, 169.4, 170.2, 170.5 (4 × CO, Ac); HR-ESIMS m/z
581.1624 (calcd for C28H30O12Na, 581.1629). The spectroscopic data
are in agreement with the anticipated structure.
General Procedure for Selective Deacetylation. Acetylated
glucosides 15−18 (0.45 mmol) were separately dissolved in a mixture
E
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Benzyl 5-(2-O-acetyl-β-D-glucopyranosyloxy)-2-hydroxyben-
zoate (2-O-acetylisotrichocarpine) (19). 19 was obtained following
the general procedure from tetraacetate 15 (269 mg, 0.47 mmol) with
15 h of reaction time and additionally recrystallized from EtOH to
give 46 mg (22%, purity >95%) of colorless crystals: Rf = 0.40
recrystallized from EtOAc/hexanes to give 92 mg (53%, purity 95%)
of colorless crystals: Rf = 0.53 (CHCl3/EtOH, 10:1); mp 93−94 °C;
[α]27 −12.5 (c 0.21, EtOH); UV (EtOH) λmax 233, 289 nm; ATR-
D
FTIR νmax 3376 (br), 2871, 1718, 1695, 1241, 1063, 1041, 763, 697
cm−1; 1H NMR (400 MHz, methanol-d4, δ, ppm, J, Hz) 3.40 (dd, 1H,
J 8.6, J 9.3, H-4Glc), 3.46 (ddd, 1H, J 2.1, J 5.5, J 9.7, H-5Glc), 3.46−
3.55 (m, 2H, H-2Glc, H-3Glc), 3.71 (dd, 1H, J 5.5, J 12.1, H-6a), 3.91
(dd, 1H, J 2.1, J 12.1, H-6bGlc), 4.92 (d, 1H, J 7.3, H-1Glc), 5.33, 5.37
(ABq, 2H, J 12.4, CH2), 7.11 (dd∼t, 1H, J 7.5, C6H4), 7.31−7.47 (m,
6H, C6H5), 7.53 (ddd, 1H, J 1.7, J 7.3, J 8.8, C6H4), 7.77 (dd, 1H, J
1.7, J 7.8, C6H4); 13C NMR (101 MHz, methanol-d4, δ, ppm) 62.5
(C-6Glc), 68.0 (CH2), 71.2 (C-4Glc), 74.9 (C-2Glc), 77.5 (C-3Glc), 78.4
(C-5Glc), 103.9 (C-1Glc), 118.8 (C-2), 122.3 (CH), 123.7 (CH), 129.3
(2 × CH, C6H5), 129.3 (CH, C6H5), 129.6 (2 × CH, C6H5), 132.1
(CH), 135.2 (CH), 137.4 (C, C6H5), 158.8 (C-1), 167.9 (CO); HR-
ESIMS m/z 413.1227 (calcd for C20H22O8Na, 413.1207). The
spectroscopic data are in agreement with the literature.26
(CHCl3/EtOH, 10:1); mp 178−180 °C; [α]29 −19.0 (c 0.17,
D
EtOH); UV (EtOH) λmax 240, 331 nm; ATR-FTIR νmax 3503 (br),
3255 (br), 2970, 2895, 1725, 1682, 1489, 1213, 1088, 1033, 787, 730
1
cm−1; H NMR (400 MHz, DMSO-d6, δ, ppm, J, Hz) 2.01 (s, 3H,
CH3, Ac), 3.27 (ddd, 1H, J 3.4, J 5.3, J 8.9, H-4Glc), 3.35 (m, 1H, H-
5Glc, overlapped with H2O peak), 3.44−3.51 (m, 2H, H-3Glc, H-6aGlc),
3.64 (dd, 1H, J 5.3, J 11.2, H-6bGlc), 4.66 (dd∼t, 1H, J 5.8, OH-6Glc),
4.72 (dd, 1H, J 8.1, J 9.3, H-2Glc), 5.00 (d, 1H, J 8.1, H-1Glc), 5.26 (d,
1H, J 5.3, OH-4Glc), 5.34−5.40 (m, 2H, CH2, OH-3Glc), 6.94 (d, 1H, J
9.0, H-5), 7.21 (dd, 1H, J 3.0, J 9.0, H-6), 7.36 (d, 1H, J 3.0, H-2),
7.36−7.49 (m, 5H, C6H5), 10.17 (s, 1H, OH); 13C NMR (101 MHz,
DMSO-d6, δ, ppm) 20.8 (CH3, Ac), 60.3 (C-6Glc), 66.6 (CH2), 69.6
(C-4Glc), 73.6 (C-2Glc), 73.8 (C-3Glc), 77.1 (C-5Glc), 99.4 (C-1Glc),
113.2 (C-3), 117.3 (C-2), 118.4 (C-5), 125.4 (C-6), 128.0 (2 × CH,
C6H5), 128.3 (CH, C6H5), 128.6 (2 × CH, C6H5), 135.6 (C, C6H5),
149.3 (C-4), 155.6 (C-1), 167.9 (CO), 169.3 (CO, Ac); HR-ESIMS
m/z 471.1251 (calcd for C22H24O10Na, 471.1262). The spectroscopic
data are in agreement with the anticipated structure.
Benzyl 2-(2-O-acetyl-β-D-glucopyranosyloxy)benzoate (2-O-ace-
tyldeoxytrichocarpine) (21). 21 was obtained following the general
procedure from tetraacetate 18 (254 mg, 0.45 mmol) with 10 h of
reaction time as colorless, amorphous solids: 24 mg (12.5%, purity
>95%); Rf = 0.66 (CHCl3/EtOH, 10:1); mp 125−126 °C; [α]27
D
−30.4 (c 0.23, EtOH); UV (EtOH) λmax 229, 285 nm; ATR-FTIR
νmax 3483 (br), 3234 (br), 2919, 1719, 1492, 1237, 1074, 1042, 749,
Benzyl 2-(β-D-glucopyranosyloxy)-5-hydroxybenzoate (tricho-
side) (8). 8 was obtained following the general procedure from
tetraacetate 17 (251 mg, 0.43 mmol) with 17 h of reaction time and
additionally recrystallized from EtOH to give 123 mg (69%, purity
95%) of colorless crystals: Rf = 0.24 (CHCl3/EtOH, 10:1); mp 159−
1
693 cm−1; H NMR (400 MHz, DMSO-d6, δ, ppm, J, Hz) 1.95 (s,
3H, CH3, Ac), 3.28 (ddd∼td, 1H, J 5.6, J 9.0, H-4), 3.45−3.54 (m,
3H, H-3Glc, H-5Glc, H-6aGlc), 3.74 (dd, 1H, J 5.3, J 10.3, H-6bGlc), 4.69
(dd∼t, 1H, J 5.6, OH-6Glc), 4.82 (dd, 1H, J 8.3, J 9.4, H-2Glc), 5.17 (d,
1H, J 8.3, H-1Glc), 5.17 (d, 1H, J 12.1, CH2), 5.26 (d, 1H, J 12.1,
CH2), 5.30 (d, 1H, J 5.4, OHGlc), 5.38 (d, 1H, J 5.5, OHGlc), 7.07
(dd∼t, 1H, J 7.2, CH, Ar), 7.21 (d, 1H, J 8.1, CH, Ar), 7.32−7.36 (m,
1H, CH, Ar), 7.41 (d, 1H, J 7.5, CH, Ar), 7.53 (dd∼t, 2H, J 7.7,
160 °C (lit. 163−165 °C);24 [α]28 −25.0 (c 0.18, EtOH); UV
D
(EtOH) λmax 233, 326 nm; ATR-FTIR νmax 3536, 3309 (br), 2938,
2875, 1725, 1500, 1206, 1070, 1020, 819, 692 cm−1. The
spectroscopic data are in agreement with the literature.24 1H NMR
(400 MHz, methanol-d4, δ, ppm, J, Hz) 3.38−3.41 (m, 2H, H-4Glc, H-
5Glc), 3.42−3.44 (m, 2H, H-2Glc, H-3Glc), 3.69 (dd, 1H, J 4.6, J 12.1,
H-6aGlc), 3.83 (dd, 4H, J 1.8, J 12.1, H-6bGlc), 3.83 (s, 3H, OMe),
4.78−4.80 (m, 1H, H-1Glc), 5.31 (s, 2H, CH2), 7.05 (d, 1H, J 9.1, H-
5), 7.32 (dd, 2H, J 3.0, J 9.1, H-6), 7.34−7.46 (m, 5H, C6H5), 7.54 (d,
1H, J 3.0, H-2); 13C NMR (101 MHz, methanol-d4, δ, ppm) 54.9
(OMe), 60.3 (C-6Glc), 65.7 (CH2), 69.2 (C-4Glc), 72.9 (C-2Glc), 75.9
(C-3Glc), 76.1 (C-5Glc), 101.4 (C-1Glc), 112.7 (C-5), 119.0 (C-2),
119.3 (C-3), 121.7 (C-6), 127.1 (2 × CH, C6H5), 127.2 (CH, C6H5),
127.6 (2 × CH, C6H5), 135.6 (C, C6H5), 150.4 (C-4), 154.2 (C-1),
165.3 (CO); HR-ESIMS m/z 443.1302 (calcd for C21H24O9Na,
443.1313). The NMR data are consistent with the structure.
C6H5), 7.67 (dd∼t, 1H, J 7.4, CH, Ar), 7.99 (d, 2H, J 8.4, C6H5); 13
C
NMR (101 MHz, DMSO-d6, δ, ppm) 21.2 (CH3, Ac), 61.0 (C-6Glc),
61.7 (CH2), 70.3 (C-4Glc), 73.9 (C-2Glc), 74.2 (C-3Glc), 77.7 (C-5Glc),
98.7 (C-1Glc), 115.6 (C-2), 122.8 (CH), 125.2 (CH), 129.3 (2 × CH,
C6H5), 129.4 (CH), 129.7 (2 × CH, C6H5), 130.0 (CH, C6H5), 130.1
(CH), 133.9 (C, C6H5), 155.1 (C-1), 166.0 (CO), 169.8 (CO, Ac);
HR-ESIMS m/z 455.1311 (calcd for C22H24O9Na, 455.1313). The
spectroscopic data are in agreement with the anticipated structure.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.jnatprod.0c00838.
Benzyl 2-(2-O-acetyl-β-D-glucopyranosyloxy)-5-hydroxy-
benzoate (2-O-acetyltrichoside) (20). 20 was obtained following
the general procedure from tetraacetate 17 (251 mg, 0.43 mmol) with
11 h of reaction time and additionally recrystallized from EtOH to
give 60 mg (30%, purity 94%) of colorless crystals: Rf = 0.47 (CHCl3/
1H NMR, 13C NMR, COSY, HSQC, HMBC, ATR-
FTIR, and UV spectra (PDF)
EtOH, 10:1); mp 178−179 °C; [α]26 −6.9 (c 0.49, EtOH); UV
D
(EtOH) λmax 232, 313 nm; ATR-FTIR νmax 3494 (br), 3262 (br),
AUTHOR INFORMATION
Corresponding Author
■
1
2900, 1719, 1501, 1272, 1210, 1083, 811, 725 cm−1; H NMR (400
MHz, DMSO-d6, δ, ppm, J, Hz) 2.02 (s, 3H, CH3, Ac), 3.26 (ddd∼td,
1H, J 5.5, J 9.4, H-4Glc), 3.38 (ddd, 1H, J 1.6, J 5.4, J 9.5, H-5Glc),
3.44−3.52 (m, 2H, H-3Glc, H-6aGlc), 3.66 (ddd, 1H, J 1.6, J 5.5, J 11.6,
H-6Glc), 3.78 (s, 3H, OMe), 4.67 (dd∼t, 1H, J 5.5, OH-6Glc), 4.73
(dd, 1H, J 8.1, J 9.5, H-2Glc), 5.04 (d, 1H, J 8.1, H-1Glc), 5.27 (d, 3H, J
5.3, OH-4Glc), 5.28 (s, 2H, CH2), 5.37 (d, 1H, J 5.5, OH-3Glc), 7.09
(d, 1H, J 9.1, H-5), 7.21 (dd, 1H, J 3.1, J 9.1, H-6), 7.26 (d, 1H, J 3.1,
H-2), 7.39 (m, 5H, C6H5); 13C NMR (101 MHz, DMSO-d6, δ, ppm)
20.9 (CH3, Ac), 56.4 (OMe), 60.4 (C-6Glc), 66.1 (CH2), 69.6 (C-
4Glc), 73.6 (C-2Glc), 73.8 (C-3Glc), 77.1 (C-5Glc), 99.1 (C-1Glc), 114.0
(C-5), 118.9 (C-2), 120.4 (C-3), 122.0 (C-6), 127.8 (2 × CH, C6H5),
128.0 (CH, C6H5), 128.5 (2 × CH, C6H5), 136.2 (C, C6H5), 150.1
(C-4), 153.8 (C-1), 164.9 (CO), 169.4 (CO, Ac); HR-ESIMS m/z
485.1410 (calcd for C23H26O10Na, 485.1418). The spectroscopic data
are in agreement with the anticipated structure.
Elena V. Stepanova − Tomsk Polytechnic University, Tomsk
634050, Russia; N. D. Zelinsky Institute of Organic Chemistry
of the Russian Academy of Sciences, Moscow 119991, Russia;
orcid.org/0000-0001-9617-9110; Email: eline_m@
mail.ru, glycoside.m@gmail.com
Authors
Dariya D. Fedorova − Tomsk Polytechnic University, Tomsk
634050, Russia
Dariya S. Nazarova − Tomsk Polytechnic University, Tomsk
634050, Russia
David L. Avetyan − Tomsk Polytechnic University, Tomsk
634050, Russia; Siberian State Medical University, Tomsk
634050, Russia
Benzyl 2-(β-D-glucopyranosyloxy)benzoate (deoxytrichocarpine)
(9). 9 was obtained following the general procedure from tetraacetate
18 (254 mg, 0.45 mmol) with 15.5 h of reaction time and additionally
Andrey Shatskiy − Tomsk Polytechnic University, Tomsk
634050, Russia; Department of Chemistry, KTH Royal
F
https://dx.doi.org/10.1021/acs.jnatprod.0c00838
J. Nat. Prod. XXXX, XXX, XXX−XXX

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M. Adv. Pharmacol. Sci. 2018, 2018, 5341487.
Institute of Technology, Stockholm 10044, Sweden;
orcid.org/0000-0002-7249-7437
Maxim L. Belyanin − Tomsk Polytechnic University, Tomsk
(16) Abedi, F.; Razavi, B. M.; Hosseinzadeh, H. Phytother. Res. 2020,
34, 729−741.
634050, Russia
̈
̈
Markus D. Karkas − Department of Chemistry, KTH Royal
Institute of Technology, Stockholm 10044, Sweden;
orcid.org/0000-0002-6089-5454
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was financially supported by the Tomsk Polytechnic
University Competitiveness Enhancement Program grant no.
203\2020 and by the KTH Royal Institute of Technology. The
Olle Engkvist Foundation is kindly acknowledged for a
postdoctoral fellowship to A.S. The TPU Shared Knowledge
Center and Aleksey Ivanov are kindly acknowledged for
assistance with UV measurements.
(22) Khatoon, F.; Khabiruddin, M.; Ansari, W. H. Phytochemistry
1988, 27, 3010−3011.
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