A selective and mild glycosylation method of natural phenolic alcohols

Article abstract of DOI:10.3762/bjoc.12.51

Several bioactive natural p-hydroxyphenylalkyl β-D-glucopyranosides, such as vanillyl β-D-glucopyranoside, salidroside and isoconiferin, and their glycosyl analogues were prepared by a simple reaction sequence. The highly efficient synthetic approach was achieved by utilizing acetylated glycosyl bromides as well as aromatic moieties and mild glycosylation promoters. The aglycones, p-O-acetylated arylalkyl alcohols, were prepared by the reduction of the corresponding acetylated aldehydes or acids. Various stereoselective 1,2-trans-O-glycosylation methods were studied, including the DDQ-iodine or ZnO-ZnCl2 catalyst combination. Among them, ZnO-iodine has been identified as a new glycosylation promoter and successfully applied to the stereoselective glycoside synthesis. The final products were obtained by conventional Zemplén deacetylation.

Full text of DOI:10.3762/bjoc.12.51

A selective and mild glycosylation method of
natural phenolic alcohols
Mária Mastihubová* and Monika Poláková
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 524–530.
Institute of Chemistry, Slovak Academy of Sciences, Dúbravská cesta
9, SK-845 38 Bratislava, Slovakia
doi:10.3762/bjoc.12.51
Received: 03 December 2015
Accepted: 01 March 2016
Published: 15 March 2016
Email:
Mária Mastihubová* - chemjama@savba.sk
* Corresponding author
Associate Editor: S. Flitsch
Keywords:
© 2016 Mastihubová and Poláková; licensee Beilstein-Institut.
License and terms: see end of document.
diastereoselectivity; p-hydroxyphenylalkyl glycosides; mild promoters;
natural products; 1,2-trans-glycosylation
Abstract
Several bioactive natural p-hydroxyphenylalkyl β-D-glucopyranosides, such as vanillyl β-D-glucopyranoside, salidroside and
isoconiferin, and their glycosyl analogues were prepared by a simple reaction sequence. The highly efficient synthetic approach was
achieved by utilizing acetylated glycosyl bromides as well as aromatic moieties and mild glycosylation promoters. The aglycones,
p-O-acetylated arylalkyl alcohols, were prepared by the reduction of the corresponding acetylated aldehydes or acids. Various
stereoselective 1,2-trans-O-glycosylation methods were studied, including the DDQ–iodine or ZnO–ZnCl2 catalyst combination.
Among them, ZnO–iodine has been identified as a new glycosylation promoter and successfully applied to the stereoselective
glycoside synthesis. The final products were obtained by conventional Zemplén deacetylation.
Introduction
Arylalkyl (substituted benzyl, phenethyl and phenylpropenyl) 4-hydroxyphenethyl β-D-glucopyranoside (salidroside, 2)
glycosides having a free phenolic function at the para-position which is known to be the main bioactive component of plants of
of the aglycone are substances widely occurring in plants. They the genus Rhodiola. 4-Hydroxy-3-methoxycinnamyl β-D-gluco-
exhibit numerous biological activities which are in many cases pyranoside (isoconiferin or citrusin D, 3) has been shown to ex-
related to their structure–antioxidant activity relationship. hibit a hypotensive effect [14] (Figure 1).
4-Hydroxy-3-methoxybenzyl β-D-glucopyranoside (vanillyl
β-D-glucoside, 1) isolated from the exocarp of Juglans mand- The activities of the above mentioned glycosides are primarily
shurica Maxim showed antibacterial activity [1]. A wide range related to the structure of the aglycone. The glycosylation of the
of pharmacological effects, e.g., anti-oxidant, anti-inflammato- poorly soluble hydroxyalkylphenols, such as 4-hydroxybenzyl,
ry, anticancer, hepatoprotective, cardioprotective, neuroprotec- vanillyl, 4-hydroxyphenethyl and coniferyl alcohols, signifi-
tive, antidiabetic, and antiviral activities [2-13] are reported for cantly increases their water solubility. Further it influences the
524

Beilstein J. Org. Chem. 2016, 12, 524–530.
Figure 1: Structures of vanillyl β-D-glucoside (1), salidroside (2) and isoconiferin (3).
physicochemical and pharmacological properties of these dases from fruit seed meals are the most commonly used biocat-
phenols and often reduces their potential toxicity. Moreover, alysts for reverse hydrolysis reactions carried out in organic
p-hydroxyarylalkyl glycosides are also key starting building media or ionic liquids as co-solvents [24-27]. The enzymatic
blocks for the synthesis of more complex bioactive natural com- transglucosylation using 4-nitrophenyl β-D-glucopyranoside as
pounds with promising therapeutic potential (e.g., phenyl- the donor and almond β-glucosidase as biocatalyst gave salidro-
propanoid glycosides) [15,16]. Therefore, the development of side (2) in moderate yield [28].
relatively simple and safe procedures is needed for a rapid
multigram-scale synthesis of arylalkyl glycosides in good Recently, we have published the enzymatic glycosylation of
yields.
tyrosol (2-(4-hydroxyphenyl)ethanol) with cellobiose, lactose
and melibiose as donors for the preparation of salidroside and
The total syntheses of compounds 1, 2 and 3 and their struc- its α- and β-galactoside analogues [31]. However, all transgly-
turally related glycosides employing various chemical [9,17-23] cosylation reactions required a distinct pair of the disaccharide
or enzymatic [24-29] methods have been previously reported. donor and the glycosidase for which the reaction conditions had
The most frequently used protocol under Koenigs–Knorr condi- to be optimized. The current paper deals with an efficient, safe
tions is represented by the reaction of an acetobromoglucose and uniform chemical synthesis of various p-hydroxyarylalkyl
and (4-O-benzyloxyphenyl)alkyl alcohol catalysed by Ag salts glycosides, including compounds 1–3.
[9,18]. The final removal of the benzyl protecting group from
Results and Discussion
the phenolic function of the aglycone by catalytic reduction can
be however problematic in the case of more complex molecules Preparation of aglycones
containing for example double bonds (e.g., arenarioside) [30]. The synthesis of the appropriate aglycones 6a–c was
Isoconiferin (3) has been prepared mainly by the trichloroacet- commenced from readily available commercial p-hydroxy-
imidate method [20,21] using 4-O-acetylated coniferyl alcohol phenylcarbaldehydes 4a–c which are less expensive than the
as the acceptor. On the other hand, the Mizoroki–Heck reaction corresponding p-hydroxybenzyl alcohols (Scheme 1). The
of 4-hydroxy-3-methoxyphenylboronic acid and peracetylated conventional acetylation of 4a–c with acetic anhydride in pyri-
allyl β-D-glucoside has been used to synthesize 3 in 52% yield dine gave p-acetoxyphenylcarbaldehydes 5a–c in more than
[22].
98% yields. Subsequently the aldehyde function was reduced by
NaBH4 at pH 7–8, which was kept constant by the continuous
Enzymatic glycosylations of arylalkyl alcohols are easily addition of 85% H3PO4 to avoid phenolic acetyl-group
accomplished, however, the glycosides have often been ob- cleavage. The p-acetoxybenzyl alcohols 6a–c were isolated in
tained in low to moderate yields (usually below 30%). Glucosi- 85–95% yields.
Scheme 1: Reagents and conditions: a) Ac2O, pyridine, rt, 10 h, >98%; b) NaBH4, H3PO4, −5 °C, 85–95%.
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Beilstein J. Org. Chem. 2016, 12, 524–530.
p-Hydroxyphenylacetic acid (7) and ferulic acid (10) are also In the course of our synthetic studies, 1,2-trans-glycosylation
more readily available on the market than the corresponding reactions utilizing per-O-acetyl-D-glucopyranose as a donor
alcohols, tyrosol and coniferyl alcohol. Therefore p-O-acety- were initially investigated. However, the reaction of 6b with
lated tyrosol (9) and p-O-acetylated coniferyl alcohol (12) were per-O-acetylated-D-glucopyranose promoted by a Lewis acid
prepared from acids 7 and 10 by a two-step sequence: acid-cata- (SnCl4) in DCM failed. The deacetylated aglycone – vanillyl
lysed acetylation of the phenolic hydroxy group (isolated yields alcohol along with some amounts of 2,3,4,6-tetra-O-acetyl-D-
>94%) followed by the reduction of the carboxylic function glucopyranose were isolated. It is evident that these frequently
with NaBH4–I2 in THF (Scheme 2). Due to the higher lability used reaction conditions require more acid-stable derivatives.
of the phenolic acetate under basic conditions, the method Therefore, it was reasonable to look for milder conditions for an
published by Kanth and Periasamy [32] was slightly modified. efficient and inexpensive method of glycosylation while
For this, the reagents were added at lower temperature, the reac- excluding the use of toxic mercury salts as promoter (Helferich
tion time was prolonged and a solution of NaHCO3 instead of reaction) or silver salts. The latter are often rather expensive,
NaOH was used for washing. Under these conditions, the moisture and light sensitive, and uncomfortable to handle.
deacetylated product was formed only in traces (<5%).
Regarding the reduction of acetylated ferulic acid 11, no forma- Accordingly, various acetylated glycosyl bromides 13, 15–20
tion of the 1,4-reduction product was observed and the double derived from pyranoses, furanoses and a disaccharide (Figure 2)
bond remained untouched.
were prepared as glycosyl donors in one step and high yields
starting from the peracetylated sugars.
Glycosylation reactions
Acetyl-protecting groups are the simplest choice also for the The glycosyl bromides depicted in Figure 2 were subsequently
protection of the glycone part since the deprotection of both, examined in the glycosylation of acceptors 6a–c, 9 and 12
sugar and aromatic moieties, can be accomplished in one step. (Scheme 3, Table 1). The choice of the glycosylation promoter
Naturally occurring O-glycosides possess mostly 1,2-trans- was strongly limited by the instability of the phenolic acetyl
glycosidic linkages. Therefore, neighbouring group participa- group under basic as well as strongly acidic conditions. Only
tion is usually exploited in the trans-O-glycosylation of appro- mild, neutral promoters were therefore selected and investigat-
priate aglycones.
ed. Thus, the reactions were performed in the presence of
Scheme 2: Reagents and conditions: a) Ac2O, H2SO4, 5 °C to rt, 30 min, >94%; b) 1. NaBH4, THF, 5 °C, 10 min, 2. I2, 5 °C, 15 min, rt, 3 h, 84% for
9, 69% for 12.
Figure 2: Synthesized glycosyl donors.
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Beilstein J. Org. Chem. 2016, 12, 524–530.
known mild catalysts such as Ag2O [33] (method A), the less halides in the 1,2-trans-glycoside synthesis [35-38]. Despite the
frequently used ZnO–ZnCl2 system [34] (method B) and the fact that the precise mechanism is not clear, it is assumed that
combination of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone the reaction of the glycosyl bromide promoted by iodine
(DDQ) with iodine (DDQ–I2) [35] (method C). In addition (through the formation of an iodobromonium ion) results in a
ZnO–I2 (method D) was successfully applied as a new promoter carbohydrate-derived oxocarbonium ion that functions as the
in the stereoselective 1,2-trans-glycoside synthesis (Table 1, reactive intermediate [35].
entries 4, 9, 13, 17, 19 and 25). The selection of methods C and
D was based on the common knowledge that iodine, either In the first step, acceptor 6b and glucopyranosyl bromide 13 as
alone or in combination with other promoters such as salts of the donor were selected and tested in the presence of the above
various metals (other than the traditional Koenigs–Knorr heavy mentioned promoters (see Table 1, entries 1–4) in order to iden-
metals), serves as an effective activator of disarmed glycosyl tify the optimal glycosylation conditions in terms of yield and
Scheme 3: General reaction scheme for the synthesis of p-hydroxyphenylalkyl glycosides.
Table 1: Synthesis of 21a–c to 30 under various conditions.
Entry
Donor
Acceptor
Methoda Mol. sieves
Temp.
Time (min)
Product
Yield (%)
α:βb
1
2
13
13
13
13
13
13
13
13
13
13
6b
6b
6b
6b
6a
6c
9
A
B
C
D
C
C
B
C
D
C
No
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
180
90
21b
21b
21b
21b
21a
21c
22
57
46
68
56
78
63
49
61
63
0:1
0:1
0:1
0:1
0:1
0:1
0:1
0:1
0:1
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
3
40
4
360
20
5
6
60
7
90
8
9
110
360
15
22
9
9
22
10
12
23
24
<5
58
n.d.
0:1
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
14
15
15
16
17
18
18
19
19
20
20
20
20
20
20
12
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
E
C
D
C
C
C
D
C
D
C
C
Cc
C
B
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
–d
rt
30
20
360
30
30
30
360
20
45
20
25
25
30
90
75
23
25
55
68
63
70
70
50
46
66
62
56
52
45
78
50
72
0:1
0:1
rt
25
0:1
rt
26
1:0
rt
27
0:1
rt
28
0:1
rt
28
0:1
rt
29
1:0
rt
29
1:0
rt
30α/β
30α/β
30α/β
30α/β
30α/β
30β
1:2.3
1:4
rt
No
rt
1:2.1
1:4.7
1:3.5
0:1
No
4 °C
4 °C
4 °C
No
D
No
aMethod: A) Ag2O; B) ZnO–ZnCl2; C) DDQ–I2; D) ZnO–I2; E) TMSOTf. bAnomeric ratios were determined by integration of the appropriate peaks in
the 1H NMR spectra; n.d. – not determined. cDCM was used as the solvent. dTemperature −78 to 0 °C.
527

Beilstein J. Org. Chem. 2016, 12, 524–530.
selectivity. In all cases, only the 1,2-trans-glycosylation prod- bond between galactose and glucose in lactosyl bromide 15 was
uct, β-glucoside 21b, was obtained. While method B not affected under the examined conditions. On the other hand,
(ZnO–ZnCl2) performed in DCM instead of ACN afforded only the reaction of D-mannosyl and L-arabinosyl bromides 16 and
a moderate yield (Table 1, entry 2, 46%) of 21b, the reactions in 19 with 6b afforded solely α-anomers 26 and 29 as the 1,2-
DCM promoted by Ag2O (Table 1, entry 1, 57%) and ZnO–I2 trans-glycosylation products. The α-manno-configuration of
(Table 1, entry 4, 56%) gave comparably good yields. DDQ–I2 glycoside 26 was proven by the characteristic coupling con-
in ACN (Table 1, entry 3, 68%) gave 21b in the highest yield, stant (1JC1,H1 = 170.3 Hz). The α-configuration of the L-arabi-
in addition to the exclusive selectivity and the shortest reaction nofuranoside 29 was confirmed by 1H NMR (broad singlet at
time (Table 1, entry 5). Therefore this promoter was selected for 5.09 ppm) and 13C NMR spectra (C-1 at 104.6 ppm).
the glucosylation reactions of acceptors 6a and 6c with bro-
mide 13, affording compounds 21a and 21c with full β-selec- In contrast to the above mentioned results, the reaction of
tivity.
D-xylosyl bromide 20 with 6b did not proceed stereoselective-
ly. An anomeric mixture of vanillyl xylosides 30α/β in a ratio
Acetylated tyrosol 9 as glycosyl acceptor reacted only smoothly varying from 1:2.3 to 1:4 was obtained when the glycosylation
with 13 under all three studied reaction conditions (Table 1, was promoted with DDQ–I2 in either DCM or ACN at room
entries 7–9) affording the acetylated salidroside 22 from moder- temperature (Table 1, entries 20–22). The same reaction per-
ate (ZnO–ZnCl2, 49%) to good yields (DDQ–I2, 61% and formed at 4 °C provided again a mixture of xylosides 30α/β
ZnO–I2, 63%) with strict β-stereocontrol.
(Table 1, entry 23) but with a slightly higher selectivity (30α/β
in ratio 1:4.7). Therefore, to improve the selectivity, other
On the other side, the glucosylation of p-O-acetylated coniferyl promoters were also examined at low temperature. The use of
alcohol 12 with bromide 13 failed under these conditions. ZnO–ZnCl2 in DCM (Table 1, entry 24) led again to a mixture
Coniferyl aldehyde 24 was detected and isolated as a major of xylosides 30α/β. In contrast, the glycosylation promoted by
product. For example, the DDQ–I2-promoted reaction provided ZnO–I2 in DCM (Table 1, entry 25) was the only condition
aldehyde 24 in 58% yield along with less than 5% of the desired affording 30 as pure β-anomer (72%). The lack of selectivity at
product 23. This may be caused by the oxidative nature of the room temperature can be explained by a higher thermodynamic
promoter and by the existence of a conjugated electronic stability of the α-xylopyranosides compared to the correspond-
push–pull system of coniferyl alcohol that is enhanced by the ing β-xylopyranosides. Apparently, anomerisation of the kineti-
electron-withdrawing acetoxy group. On the contrary, the cally formed β-anomer easily takes place under mild reaction
TMSOTf-promoted glycosylation [39] (method E) of coniferyl conditions at ambient temperature [40], but it is suppressed by
alcohol 12 with trichloroacetimidate 14 at low temperature was decreased temperature in combination with an appropriate
found to be more efficient and glycoside 23 was obtained in promoter (ZnO–I2). Moreover, this new promoter was success-
high yield with full β-selectivity as proved by NMR spectrosco- fully applied to the reactions of the corresponding acceptor and
py. The phenolic acetyl group remained intact under these four other glycosyl bromides, i.e., D-glucosyl (Table 1, entries 4
conditions.
and 9), D-galactosyl (Table 1, entry 13), lactosyl (Table 1, entry
17) and L-arabinosyl (Table 1, entry 19). The glycosylation
Six distinct acetylated glycosyl donors 15–20 were further ex- reactions of the latter donors catalysed by ZnO–I2 gave compa-
amined to prove the feasibility of the method. D-Galacto-, rable yields and were completely stereoselective similarly to
D-manno- and methyl D-glucuronate-derived donors 15–17 other promoters, although they required at least a 2-times longer
originated from hexopyranoses. The pentosyl donors, which reaction time.
usually exhibit a diminished glycosylation selectivity, were
represented by L-arabinofuranosyl bromide 19 and D-xylopyra- In the final step, the removal of the acetyl groups under
nosyl bromide 20.
Zemplén conditions proceeded smoothly and the desired target
glycosides 1–3, 31a,b and 32–37 were isolated in high yields
The glycosylation of 6b with galactosyl, glucuronic acid methyl (Figure 3).
ester or lactosyl bromides 15, 17 and 18, proceeded also stereo-
selectively and the β-anomers of glycosides 25, 27 and 28 were Conclusion
isolated in good yields (50–68%) as the only products. The The glycosylation methods studied in this work represent a
structures of all β-anomers (21a–c, 22, 23, 25, 27 and 28) were simple and convenient approach to bioactive natural p-hydroxy-
confirmed by the presence of a doublet of the anomeric proton phenylalkyl glycosides and their analogues. The mild reaction
with characteristic vicinal interaction constant 3J1,2 in the conditions with exclusive stereoselectivity can be used as an al-
interval of 7.5–7.9 Hz in the 1H NMR spectra. The glycosidic ternative to the common Koenigs–Knorr or Helferich glycosyla-
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Beilstein J. Org. Chem. 2016, 12, 524–530.
Figure 3: Overview of protected and deprotected products.
tion. In many cases, the DDQ–I2-promoted reaction provided Acknowledgements
products in a stereoselective way and in the highest yields. It is This work was supported by the Slovak Research and Develop-
noteworthy that ZnO–I2 is a new glycosylation promoter, which ment Agency under the contract No. APVV-846-12, the Scien-
was found to well activate also less reactive disarmed tetra-O- tific Grant Agency of the Ministry of Education of Slovak
acetyl-α-D-glycopyranosyl bromides, to give stereoselectively Republic and Slovak Academy of Sciences (VEGA) under the
only the 1,2-trans glycosides in good to high yields. These project No. 2/0138/12 and the Research & Development Opera-
conditions were efficiently used in the stereoselective xyloside tional Programmes funded by the ERDF („Centre of Excel-
synthesis that is not trivial. All used glycosylation conditions lence on Green Chemistry Methods and Processes“, CEGreenI,
were compatible with acetyl protective groups of the phenolic Contract No. 26240120001 as well as „Amplification of the
function. The coupling reaction and deprotection were achieved Centre of Excellence on Green Chemistry Methods and Pro-
in two steps, thus providing the rapid access to the targeted cesses“, CEGreenII, Contract No. 26240120025). The authors
glycosides.
thank I. Uhliariková for NMR measurements, S. Bekešová and
S. Vlčková for mass measurements.
Supporting Information
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