Synthesis of aryl α-O-L-rhamnopyranoside by two-step reaction in one pot

DOI: 10.1080/07328303.2017.1390578

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Journal of Carbohydrate Chemistry p. 220 - 234 (2017)

Update date:2022-08-04

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Authors:

Liu, Nianping

Tian, Xiangguang

Ding, Zekun

Zhou, Yongda

Zhang, Wan

Wang, Qingbing

Zhang, Yi

Gu, Yijun

Zhang, Jianbo

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Article abstract of DOI:10.1080/07328303.2017.1390578

The title compounds were conveniently synthesized by a phase transfer catalyzed approach in two steps and one pot using the rhamnopyranosyl chloride as key intermediate. The twostep one-pot procedure is more convenient and environmentally friendly, compared to the published synthetic routes. Besides, the structure-reactivity relationship and the plausible mechanism for this base-catalyzed glycosylation were discussed bymeans of the Hammett equation.

Full text of DOI:10.1080/07328303.2017.1390578

Journal of Carbohydrate Chemistry

ISSN: 0732-8303 (Print) 1532-2327 (Online) Journal homepage: http://www.tandfonline.com/loi/lcar20

Synthesis of aryl α-O-L-rhamnopyranoside by two-

step reaction in one pot

Nianping Liu, Xiangguang Tian, Zekun Ding, Yongda Zhou, Wan Zhang,

Qingbing Wang, Yi Zhang, Yijun Gu & Jianbo Zhang

To cite this article: Nianping Liu, Xiangguang Tian, Zekun Ding, Yongda Zhou, Wan

Zhang, Qingbing Wang, Yi Zhang, Yijun Gu & Jianbo Zhang (2017): Synthesis of aryl α-O-L-

rhamnopyranoside by two-step reaction in one pot, Journal of Carbohydrate Chemistry, DOI:

10.1080/07328303.2017.1390578

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Date: 07 November 2017, At: 04:03

JOURNAL OF CARBOHYDRATE CHEMISTRY

, VOL. , NO. , –

https://doi.org/./..

Synthesis of aryl α-O-L-rhamnopyranoside by two-step

reaction in one pot

Nianping Liu^a, Xiangguang Tian^a, Zekun Ding^a, Yongda Zhou^a, Wan Zhang^a,

Qingbing Wang^a, Yi Zhang^a, Yijun Gu^b,§, and Jianbo Zhang^a

^aDepartment of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University,

Shanghai, China; ^bDivision of TCM informatics, The Shanghai Innovative Research Center of Traditional

Chinese Medicine, Shanghai, China

ABSTRACT

ARTICLE HISTORY

Received  July 

Accepted  October 

The title compounds were conveniently synthesized by a phase

transfer catalyzed approach in two steps and one pot using

the rhamnopyranosyl chloride as key intermediate. The two-

step one-pot procedure is more convenient and environmentally

friendly, compared to the published synthetic routes. Besides, the

structure-reactivity relationship and the plausible mechanism for

this base-catalyzed glycosylation were discussed by means of the

Hammett equation.

KEYWORDS

Rhamnoside;

rhamnopyranosyl chloride;

phase transfer catalysis;

α-O-aryl rhamnoside

GRAPHICAL ABSTRACT

Introduction

Aryl α-L-rhamnosides are important functional biomolecule in glycobiologi-

cal researches.^[1–7]For instance, para-nitrophenyl α-L-rhamnopyranoside, which

releases para-nitrophenol in the presence of α-L-rhamnosidase, is featured with

its chromogenic properties.^[7–9]It can also serve as a synthetic intermediate in

enzymatic glycosylation for the preparation of other rhamnosides and bioactive

compounds.^[10–12]

Several preparation methods for the aryl α-L-rhamnoside have been reported in

the literature.^[13]As a classic synthetic method towards glycosides, Köenigs-Knorr

reaction was ﬁrst applied to the target compounds by Shintaro Kamiya et al.^[14]

However, highly poisonous mercuric cyanide and mercuric bromide were used as

catalysts in this synthesis, and furthermore the overall yield was rather low. The

CONTACT J. Zhang

jbzhang@chem.ecnu.edu.cn

Normal University, Shanghai , China.

School of Chemistry and Molecular Engineering, East China

^§Presentaddress:Room, Building, YueyangRoad, ShanghaiInstituteofBiochemistryandCellBiology/National

Center of Protein Sciences Shanghai, Chinese Academy of Sciences, Shanghai , China.

Color versions of one or more of the ﬁgures in the article can be found online at www.tandfonline.com/lcar.

N. LIU ET AL.

Scheme . Synthesis of α-O-aryl L-rhamnopyranoside.

same authors also reported the use of Helferich glycosylation for the synthesis as

a modiﬁcation. As a result, this shortened the synthesis to three steps, where the

glycosylation reaction was successfully catalyzed by p-toluenesulfonic acid, anti-

monyl trichloride or other Lewis acids. The glycosylation yields ranged from 40

to 60%. The same type of reaction was also reported by Westphal, Garegg and

Nishio,^{[7, 15, 16]}with ZnCl₂, SnCl₄and BF₃·OEt₂as catalysts, and the glycosylation

yields were 38%, 53% and 36.4%, respectively. Apparently, in these synthetic meth-

ods either the involved reagents were highly toxic or the reactions were not easy to

handle as strictly anhydrous condition was required.

With the purpose of developing an eco-friendly synthetic strategy, a series of

methods were explored by our group.^[17]A convenient and eﬀective method was

ﬁnally found, in which the title compounds were synthesized in only two steps

(Scheme 1). Initially, L-rhamnose (1) was acetylated and chlorinated in the presence

of acetyl chloride to prepare 2,3,4-tri-O-acetyl-α-L-rhamnosyl chloride (2); then

2 was directly converted into the target molecule 3 under phase transfer catalytic

condition.

Results and discussion

A single-step synthesis of aromatic α-D-glucoside was reported.^[18–20]We wanted

to applied it to the direct synthesis of aromatic α-L-rhamnoside, but the attempt

failed. Thus, we came up with a two-step method using the glycosyl halide as the

key intermediate. As far as we are concerned, glycosyl chloride and bromide are one

of the most commonly applied glycosylation reactions. Compared with rhamnosyl

chloride, rhamnosyl bromide is more easily decomposed under most glycosylation

conditions, so we tried to applied rhamnosyl chloride as glycosyl donor in the syn-

thesis of aromatic α-L-rhamnosides in consideration of its stability and convenient

preparation method.^[21–24]The previous strategies to obtain rhamnosyl chloride

Scheme . Synthetic strategies towards rhamnosyl chloride.

JOURNAL OF CARBOHYDRATE CHEMISTRY

were usually focused on indirect methods (Scheme 2), which are time consuming

synthetic procedures.^{[23, 25–27]}

In order to circumvent this problem, we carried out the acetylation step with

acetic anhydride and acetic chloride under acidic conditions using H₂SO₄/SiO₂as

catalyst, which allowed for chlorination as well, to establish a one-pot synthetic

route (Scheme 2)with a good yield (67.5%). This method has advantages including

short route, simple operation, and non-use of toxic reagent, and solvent-free condi-

tion. Here, acetyl chloride was employed as both an acetylating and a chlorinating

reagent for L-rhamnose_.Modest heating condition (room temperature to 35 °C) was

required to initiate the reaction, and then the reaction was spontaneously acceler-

ated by the catalyst. The rhamnosyl chloride 2 was characterized with ¹H NMR.^[26]

Inspired by the alkaline condition for deacetylation and the glycosylation

method we have developed in alkaline systems,^[9]we explored to achieve gly-

cosylation and deacetylation steps in the same vessel. Diﬀerent alkaline systems,

such as CH₃ONa/CH₃OH, NaOH/H₂O, pyridine/H₂O, etc, were examined.^[28]The

CH₃ONa/CH₃OH and pyridine/H₂O systems could rarely oﬀer the target product.

The NaOH/H₂O system only resulted in a little amount of the product with too

many by-products. In order to improve the yield, we tried phase transfer catalyst

(PTC) condition,^[28]which gave good results. Thus, the CTAB/NaOH/H₂O system

was further optimized using a model reaction (T able 1).

Initially, we tried the reaction of 2 with phenol (4a) (T able 1) in the presence

of 0.3 equiv. of cetyltrimethyl ammonium bromide (CTAB) as the phase transfer

catalyst and 10% NaOH as the promoter in CH₂Cl₂at 20 °C, which gave a 25.6%

yield. Next, we examined the inﬂuence of the amount of phenol on the glycosylation.

As is demonstrated in T able 1, with the equivalency of phenol ranging from 1.1 to

2.0, the reaction proceeded rather slowly and the yields were low. In addition, the

formation of by-products increased when the reaction time was lengthened (entries

2–3). We also found that with 2.5 equiv. of phenol, the reaction proceeded well and

the product was obtained in acceptable yield (entry 4). However, the yield of the

desired compound 5a did not increased dramatically when 3.0 equiv. of phenol was

utilized (entry 5).

Subsequently, we explored the inﬂuence of diﬀerent phase transfer catalysts,

such as tetrabutyl ammonium bromide (TBAB), cetyltrimethyl ammonium bro-

mide (CTAB), benzyltriethyl aminium chloride (TEBA) and tetrabutyl ammonium

hydrogen sulfate (TBAHS), and further optimized the conditions (entry 4 and 6–

12).^[21]It was indicated that 0.2 equiv. of TBAB (entry 10) greatly promoted the

reaction, considering the yield and time-eﬃciency.

In addition, the type and equivalency of the base used in the system were also

explored (entry 10 and entries 13–18). We tried diﬀerent bases such as NaOH,

NaCO₃, Bu₄NOH and KOH in 7.5 equiv., and the results showed NaOH was the

best. Next, we tested diﬀerent equivalencies of NaOH (entry 10 and entries 16–

18). Apparently, 7.5 equiv. of 10% NaOH was superior. It is noteworthy that the

yield improved dramatically when 10% NaOH was added into the system in batches

instead of addition at once (entries 10 and 19–23), and the 1:1:1 volume ratio of

batches gave the optimal results.

N. LIU ET AL.

Table . Optimization of the glycosylation reaction with PTC.

Batch addition method

Entry Eq. (phenol) PTC Eq. (PTC) Base Eq. (base)

of base (v/v)

T (°C) Time (h) Yield (%)^a

















.

.

CTAB

TBAB

TEBA

TBAHS

TBAB

.

.

.

.

.

.

NaOH

Na_CO_

Bu_NOH

KOH

NaOH

.

.

.

.

.

: ^c

:

:







































.

.

.

.

.

.

.

.

.

.

.

.

n.d^b

n.d

.

.

.

.

.

.

.

.

.

—

.

.

.

.





































:

:

:

::





.

—



^aIsolated yield ^bNot detected ^cAdding base into the reaction system at one-time or in batches, for example, : means

batch adding at volume ratio of :

Finally, we explored the inﬂuence of temperature on the reaction ranged from 0

to 40°C (entries 23–26). The best result was achieved when the glycosylation was

treated at room temperature (entry 25). Satisfactorily, with TBAB (0.2 equiv) as the

phase transfer catalyst, 10% NaOH (7.5 equiv.) as the promoter that was added into

the reaction system in batches and CH₂Cl₂as solvent, the reaction at 30 °C could

aﬀord 5a in a 90% overall yield (T able 1, entry 25).

Encouraged by these results, we further extended the scope of this reaction to

a series of phenols 4a-4o as glycosyl acceptors, as illustrated in T able 2 (entries

1–15). The reactions proceeded completely in 4.5–6 hours in good to excellent

yields (63.6%–98.2%) for both the phenols with electron-withdrawing substituents

(entries 2–8) and the phenols with electron-donating substituents (entries 13–15),

as well as those with hindered substituents (entries 9–12). All the structures of prod-

ucts were conﬁrmed by NMR and HR-MS data.

Besides, we further ascertained the stereochemical property and bioactivity

of para-nitrophenyl α-L-rhamnopyranoside 5g as a representative glycosylation

JOURNAL OF CARBOHYDRATE CHEMISTRY

Table . Scope of the phase-transfer catalyzed glycosylation^a.

Entry



Acceptor

Product

Time (h)



Yield (%)^b

.







.

.





.



.

.





.



.

.

.

.









.

.







.

.









.



.

.

.

^aReaction conditions: TBAB (. equiv.), rhamnosyl chloride (. equiv.) phenols (. equiv.), batch adding %NaOH,

CH_Cl_, °C ^bIsolated yield.

N. LIU ET AL.

product. The compound was recrystallized from 95% ethanol via solvent evap-

oration at room temperature as colorless bulk crystals. The crystal structures

were determined to ﬁnd out their stereochemistry and solid-state conformations.

Crystal data and structural reﬁnement are speciﬁed in elsewhere,^{[7, 9]}which con-

ﬁrmed the α-conﬁguration of the product. Additionally, the enzymatic hydroly-

sis assay was also tested to conﬁrm its bioactivity and stereochemistry.^{[4, 29]}The

enzymatic hydrolysis of 5a was carried out in 0.05 M acidic acid/sodium acetate

buﬀer (pH 4.0, 4.5 and 5.0) with incubation at 40 °C. In the reaction proce-

dure, the hydrolytic rate of the rhamnoside kept constant with the authentic com-

pound. One unit of enzymatic activity was deﬁned as the amount, which released

1 mol of para-nitrophenol per minute in the buﬀer (pH 4.0), which is consistent

with the reported activity of the commercial naringinase (EC 3.2.1.40). There-

fore, all the results showed that the product we obtained is alpha-conﬁguration

anomer.

Table . Reaction of rhamnosyl chloride with phenols on large scales.

Entry

Product

Time(h)



Yield(%)^a

.









.









.

.







.

.









.

.



^aIsolated yield.

JOURNAL OF CARBOHYDRATE CHEMISTRY

Furthermore, it is crucial for the reactions to achieve on large scales. As described

in T able 3, it was shown that 2 was glycosylated with diﬀerent phenols on three-

grams scales to aﬀord satisfactory yields, which provided the evidence for the indus-

trial application of the synthetic method.

Notably, as shown in T able 2, it was evident that substituents exerted a signiﬁ-

cant inﬂuence on the reaction yields. The results indicated that electro-withdrawing

substituents reduced the yields, while electron-donating substituents gave excellent

results. However, inﬂuential factors on the reaction yield are rather complex. Herein,

we reported our studies about the impact of para-substituents in the phenols on the

ﬁnal yields (T able 4).

Because the k/k_His proportional to the yield/yield_H, we chose yield/yield_Has the

substitution plugging into Hammett equation and drew the corresponding Ham-

mett curve.^[30–32]However, when we chose classical constant σ to plug into the

Hammett equation, we obtained an unsatisfactory linear correlation coeﬃcient

(R²= 0.9571). Based on this result, we suspected that the nucleophiles of this

reaction was not the phenol molecules (ArOH) but the phenolic anions (ArO⁻),

which was formed as an extremely strong nucleophile when phenol contained strong

electron-withdrawing functional group such as nitro, as the acceptors during gly-

−

cosylation progress. Thus, we needed to introduce another constant σ to ﬁt the

Hammett equation.^[30–32]Under this condition, we found that the para-substituent

constants could ﬁt the Hammett equation with superb linear relationship (R²=

0.9977), as depicted in Figure 1.^[30–34]

Therefore, we proposed a plausible mechanism for the new PTC synthesis of aryl

α-L-rhamnoside as depicted in Scheme 3.^[27]First, the reaction proceeded quickly

via the formation of a glycosyl cation that could be stabilized by the neighboring

acetyl group at O-2 via the formation of an oxacarbenium ion intermediate. As a

Table . The reaction rates of para-substituent phenols and substituent constants^a.

Entry



Substituent

p-OCH_

Yield, %

.

Yield/Yield _H

.

lg(Yield/Yield_H)

.

σ_p

−.



p-CMe_

p-CH_

p-C_H_

p-H

.

.

.

.

.

.

.

.

.

.

.



.

.

−.

−.

.









−.







p-F

.

.

.

.

−.

−.

−.

−.

−.

.

p-Cl



^c

p-Br

.

.

p-NO_

^aPhenolsandaniliniumionswherealonepairofelectronsontheO-orNH_-groupcouldbedelocalizedintosubstituents.

This problem was solved by deﬁning a new constant σ_p⁻obtained from the phenol or aniline data distinguished from

classic constant σ_p.

N. LIU ET AL.

Figure . Hammett curve of the reaction of ,,-tri-O-acetyl-α-L-rhamnosyl chloride with phenols^a.

^alinear correlation coeﬃcient R^= ..

Scheme . A plausible mechanism for PTC synthesis of aryl α-L-rhamnoside involving the neighbor-

ing group participation.

result, this reactive intermediate could only be glycosidated by the attack of phe-

nolic anion formed under the phase transfer catalyst condition from the backside,

which is the rate-determining step. This can explain the unique α-selectivity and

high yield of glycosides, as well as the inﬂuence of substituents in the phenol on

the reaction yields. At last, the deacetylation reaction was completed to obtain the

desirable products. Therefore, the nucleophilicity of nucleophilic reagent is of great

signiﬁcance in this one-pot glycosylation.

Conclusion

In brief, we have successfully developed an eﬃcient and green method for the syn-

thesis of aromatic rhamnosides under PTC conditions with TBAB as the catalyst and

10% NaOH as the promoter, which was achieved in CH₂Cl₂at 30 °C. This synthetic

method has the features, such as easy accessibility of all regents used, avoiding the

utilization of heavy metallic salt or other toxic reagents, short reaction steps, simple

JOURNAL OF CARBOHYDRATE CHEMISTRY

workup procedures and high yield, as compared with previous approaches. It is a

novel synthetic method that may have industrial scale applications.

Experimental

General Methods

¹H NMR spectra were recorded on a Bruker DRX-500 (500 MHz) spectrometer

with Me₄Si as internal standard. Mass spectra were detected on Agilent 5973N and

Agilent 6120 EI mass spectrometer. Elemental analyses were taken on a Vario El

III instrument. All the reagents were purchased with purity of AR. All the reac-

tions were monitored using TLC on silica gel HF₂₅₄[10–40 µm, Yantai, China

(0.2 mm)]. Reaction products were puriﬁed by ﬂash chromatography using Silica gel

60 (300–400 mesh or 100–200 mesh, Yantai, China). Authentic para-nitrophenyl-

α-L-rhamnoside for enzymatic assay was from SIGMA (St. Louis, Missouri). α-L-

rhamnosidase was Penicillum decumbens naringinase from SIGMA (St. Louis, Mis-

souri), which speciﬁc activity is 300 U/g.

2,3,4-tri-O-acetyl-α-L-rhamnopyranosyl chloride (2)

1.00 g rhamnose·H₂O (1) (5.49 mmol) and 4.7 ml CH₃COCl (65.9 mmol) were

stirred for 15hr with an oil bath heated at 35 °C at the beginning stage for 1h.

Nitrogen atmosphere was needed to protect the reaction. Then the mixture was

diluted by dichloromethane and washed by saturated sodium bicarbonate, dried

over anhydrous Na₂SO₄and evaporated to a brown yellow syrupy, which was puri-

ﬁed by column chromatography. After chromatography, a yellowish syrupy 1.32 g

was obtained. Yield: 67.5%. Colorless crystalloid could be obtained after recrystal-

lized from petroleum ether: ethyl acetate = 1:1 (1.27 g, 65%).

¹H-NMR (CDCl₃, 500 MHz): δ 5.94(d, 1H, Ј = 2 Hz), 5.57(dd, 1H, Ј = 4, 10 Hz),

5.39(s, 1H), 5.14(t, 1H, Ј = 9.5 Hz), 4.18(m, 1H), 2.16, 2.08, 2.00(3s, 9H), 1.27(d, 3H,

Ј = 6.2 Hz).

p-nitrophenyl-α-L-rhamnoside (3)

0.78 mL10%NaOH aqueous was dropped slowly into a mixture of 251 mg

2,3,4-tri-O-acetyl-α-L-rhamnosyl chloride (0.81 mmol), 282 mg para-nitrophenol

(2.03 mmol), 89 mg cetyl alkyl trimethyl ammonium bromide (0.24 mmol) and 5 mL

CH₂Cl₂. Two hours later, 1.10 mL 10% NaOH aqueous was added slowly into reac-

tion system in batches in the next 6 hours.

The reaction was detected by thin layer chromatography until the glycosyl chlo-

ride disappeared. Then the reaction mixture was directly separated by ﬂash chro-

matography and 74.4 mg white powder was obtained in yield of 32%. It can be

recrystallized from absolute methanol to give the title compound in yield of 36%

(72.5 mg). Mp: 179–180°C.

N. LIU ET AL.

¹H-NMR (CD₃OD, 500M Hz): δ 8.22(m, 2H), 7.25(m, 2H), 5.60(d, 1H, Ј =

2.0 Hz), 4.03(q, 1H, Ј = 2, 4 Hz), 3.84(q, Ј = 3.3 Hz, 1H), 3.55 (m, 1H), 3.48 (t,

1H, Ј = 9.5 Hz), 1.22(d, 3H, Ј = 6.0 Hz);

¹³C-NMR (CD₃OD, 125M Hz): δ 150.83, 141.85, 124.75, 115.62, 98.01, 71.62,

70.15, 69.75, 69.34, 16.07.

Elemental Analysis: Calcd. for C₁₂H₁₅NO₇·CH₃OH: C, 49.21; H, 6.04; N,

4.42. Found: C, 49.27; H, 5.82; N, 4.82 (Crystal from methanol). Calcd. for

C₁₂H₁₅NO₇·H₂O: C, 47.53; H, 5.65; N, 4.62. Found: C, 47.77; H, 5.52; N, 4.62 (Crys-

tal from PE/EA).

Hydrolysis of para-nitrophenyl-α-L-rhamnoside by α-rhamnosidase

A reaction mixture consisting of 0.2 ml of 10 mM para-nitrophenyl-α-rhamnoside

(3), 0.1 ml sodium acetate buﬀer (pH 4.0, 4.5 and 5.0) and 0.2 ml of enzyme solution

was incubated at 40°C. The reaction was terminated by the addition of 2 ml of 1.0 M

Na₂CO₃. The absorbance of para-nitrophenol was measured at 400 nm. One unit

of enzymatic activity was deﬁned as the amount, which liberated 1 µmol of para-

nitrophenol per minute under pH 4.0.

phenyl-α-L-rhamnoside (5a)

¹H-NMR (CD₃OD, 500M Hz): δ 7.27(m, 2H); 7.06(m, 2H); 6.99(t,1H, J = 7.4 Hz),

5.42(s,1H);4.00(q,1H, J = 1.8 Hz); 3.85(q,1H, J = 3.4 Hz); 3.65(m,1H), 3.47(t,1H,

J = 9.5 Hz); 1.23(d,3H, J = 6.2 Hz);

ESI-LRMS: Calcd for C₁₂H₁₆O₅Na (M+Na⁺) 263.07, found 263.00

p-bromophenyl-α-L-rhamnoside (5b)

¹H-NMR (CD₃OD,500M Hz): δ 7.42 (d, 2H, J = 8.0 Hz), 7.01(d, 2H, J = 9.0 Hz),

5.40(s, 1H), 3.99(s, 1H), 3.82(q, 1H, J = 3.3 Hz), 3.60(m, 1H), 3.45(t, 1H, J = 9.5 Hz),

1.22(d, 3H, J = 6.0 Hz)

¹³C-NMR (CD₃OD, 125 MHz): δ155.9, 133.4, 119.4, 115.3, 99.9, 73.7, 72.1, 71.9,

70.8, 18.0;

ESI-LRMS: Calcd for C₁₂H₁₅BrO₅(M+H⁺) 318.01, found 318.25

p-chlorophenyl-α-L-rhamnoside (5c)

¹H-NMR (CD₃OD, 500 MHz): δ 7.28 (m, 2H), 7.05(m,2H), 5.40(s,1H), 3.98(dd,1H,

J = 3.3 Hz), 3.81(q,1H, J = 3.3 Hz), 3.60(m,1H), 3.43(t,1H, J = 9.5 Hz), 1.22(d,3H,

J = 6.2 Hz);

¹³C-NMR (CD₃OD,125 MHz): δ 156.5, 130.4, 128.0, 118.9, 99.9, 73.7, 72.1, 71.9,

70.7, 18.0;

ESI-LRMS: Calcd for C₁₂H₁₅ClO₅Na (M+Na⁺) 297.05, found 296.90

JOURNAL OF CARBOHYDRATE CHEMISTRY

2,4-di-chlorophenyl-α-L-rhamnoside (5d)

¹H-NMR (CD₃OD,500 MHz): δ7.43(d,1H, J = 8.0 Hz), 7.24(m,2H), 5.48(s,1H),

4.06(d,1H, J = 1.25 Hz), 3.89(q, 1H, J = 3.3 Hz), 3.60(m,1H), 3.46(t, 1H, J = 9.5 Hz),

1.22(d,3H, J = 7.0 Hz);

¹³C-NMR (CD₃OD, 125 MHz): δ152.0, 130.8, 128.9, 128.3, 125.5, 118.7, 100.4,

73.5, 72.1, 71.8, 71.2, 17.9;

ESI-LRMS: Calcd for C₁₂H₁₅Cl₂O₅(M+H⁺) 309.0, found 309.2

p-ﬂurophenyl-α-L-rhamnoside (5e)

¹H-NMR (CD₃OD, 500 MHz): δ 7.00(d, 2H, J = 9.0 Hz), 6.94(t, 2H, J = 17.4 Hz),

5.38(s, 1H), 4.05(d,1H, J = 1.25 Hz), 3.88(q, 1H, J = 3.3 Hz), 3.67(m, 1H), 3.49(t,

1H, J = 9.5 Hz), 1.23(d, 3H, J = 6.2 Hz)

ESI-LRMS: Calcd for C₁₂H₁₅FO₅Na (M+Na⁺) 281.08, found 280.98

3,5-diﬂurophenyl-α-L-rhamnoside (5f)

¹H-NMR(CD₃OD, 500 MHz): δ 6.65 (m, 2H),6.51(m, 1H), 5.44(s, 1H), 4.02(s, 1H),

3.82(q, 1H, J = 3.4 Hz), 3.58(m, 1H), 3.35(t, 1H, J = 9.5 Hz),1.23(d, 3H, J = 6.2 Hz)

ESI-LRMS: Calcd for C₁₂H₁₄F₂O₅Na (M+Na⁺) 299.07, found 299.14

p-nitrophenyl-α-L-rhamnoside (5g)

¹H-NMR (CD₃OD, 500 MHz): δ 8.22(m, 2H), 7.25(m, 2H), 5.60(d, 1H, Ј = 2.0 Hz),

4.03(dd, 1H, Ј = 2.0, 4.0 Hz), 3.84(q, 1H, Ј = 3.4 Hz), 3.55 (m, 1H), 3.48 (t, 1H, Ј =

9.5 Hz), 1.22(d, 3H, Ј = 6.2 Hz)

ESI-LRMS: Calcd for C₁₂H₁₅ClO₅Na (M+Na⁺) 297.05, found 296.90

2- naphthyl-α-L-rhamnoside (5h)

¹H-NMR (CD₃OD, 500 MHz): δ7.78 (d, 2H, J = 8.8 Hz), 7.73(d, 1H, J =

8.2 Hz),7.47(d, 1H, J = 1.8 Hz),7.42(t, 1H, J = 1.5 Hz),7.33(t, 1H, J =

15.0 Hz),7.20(q, 1H, J = 8.9 Hz), 5.59(s, 1H), 4.08(t, 1H, J = 2.7 Hz),3.93(q, 1H,

J = 3.4 Hz), 3.71(m, 1H), 3.49(t, 1H, J = 9.5 Hz),1.25(d, 3H, J = 6.2 Hz);

ESI-LRMS: Calcd for C₁₆H₁₈O₅Na (M+Na⁺) 313.10, found 313.08

o-methylphenyl-α-L-rhamnoside (5i)

¹H-NMR (CD₃OD, 500 MHz): δ 7.12(m,3H); 6.89(t, 1H, J = 6.9 Hz); 5.43(s, 1H);

4.04(s, 1H); 3.90(q, 1H, J = 3.4 Hz); 3.63(m, 1H); 3.47(t, 1H, J = 9.5 Hz); 2.22(s,

3H), 1.24(d, 3H, J = 6.2 Hz).

ESI-LRMS: Calcd for C₁₃H₁₉O₅Na (M+H⁺) 255.1, found 255.6

N. LIU ET AL.

o-acetylphenyl-α-L-rhamnoside (5j)

¹H-NMR (CD₃OD, 500 MHz): δ7.63(m, 1H), 7.46(m, 1H), 7.33(d, 1H, J = 8.0 Hz),

7.06(dd, 1H, J = 11.0 Hz), 5.56(d, 1H, J = 1.5 Hz), 4.10(t, 1H, J = 2.7 Hz), 3.88(q,

1H, J = 3.5 Hz), 3.62(q, 1H, J = 6.5 Hz), 3.50(t, 1H, J = 9.5 Hz), 2.59(s, 3H), 1.25(d,

3H, J = 6.5 Hz)

ESI-LRMS: Calcd for C₁₄H₁₈O₆Na (M+Na⁺) 305.10, found 305.17

5-methyl-2-nitrophenyl-α-L-rhamnoside (5k)

¹H-NMR (CD₃OD, 500 MHz): δ7.75(d, 1H, J = 8.5 Hz), 7.26(s, 1H), 6.97(d, 1H,

J = 8.0 Hz), 5.59(d, 1H, J = 1.5 Hz), 4.04(q, 1H, J = 2.0 Hz), 3.87(q, 1H, J = 3.5 Hz),

3.64(d, 1H, J = 6.0 Hz), 3.47(t, 1H, J = 9.5 Hz), 2.42(s, 3H), 1.24(d, 3H, J = 6.5 Hz)

ESI-LRMS: Calcd for C₁₃H₁₇NO₇Na (M+Na⁺)322.09, found 322.17

2,6-dimethoxyl-4-aldehydephenyl-α-L-rhamnoside (5l)

¹H-NMR(CD₃OD,500 MHz): δ9.86(s, 1H), 7.22(s, 1H), 5.39(d, 1H, J = 1.5 Hz),

4.23(d, 1H, J = 3.5 Hz), 4.14(q, 1H, J = 3.3 Hz), 3.89(d, 6H, J = 3.5 Hz), 3.83(s, 1H),

1.21(d, 3H, J = 6.5 Hz)

ESI-LRMS: Calcd for C₁₅H₂₀O₈Na (M+Na⁺) 351.11, found 351.17

p-methoxylphenyl-α-L-rhamnoside (5m)

¹H-NMR (CD₃OD, 500 MHz): δ6.98(d, 2H, J = 6.9 Hz), 6.86(d, 2H, J = 6.8 Hz),

5.29(s,1H), 3.98(s, 1H), 3.82(s, 1H), 3.75(s, 3H), 3.68(q, 1H, J = 6.5 Hz), 3.45(t, 1H,

J = 9.5 Hz), 1.23(d, 3H, J = 6.5 Hz);

ESI-LRMS: Calcd for C₁₃H₁₈O₆Na (M+Na⁺) 293.10, found 293.08

p-tert-butylphenyl-α-L-rhamnoside (5n)

¹H-NMR (CD₃OD, 500 MHz): δ7.31(d, 2H, J = 8.8 Hz), 6.97(d, 2H, J = 8.8 Hz),

5.37(d, 1H, J = 1.5 Hz), 3.98(q, 1H, J = 9.7 Hz), 3.84(q, 1H, J = 3.5 Hz), 3.66(q, 1H,

J = 1.4 Hz), 3.45(t, 1H, J = 9.5 Hz), 1.29(s, 10H), 1.23(d, 3H, J = 6.2 Hz).

ESI-LRMS: Calcd for C₁₆H₂₄O₅Na (M+Na⁺) 319.15, found 319.09

p-methylphenyl-α-L-rhamnoside (5o)

¹H-NMR (CD₃OD, 500 MHz): δ7.07(d, 2H, J = 8.3 Hz), 6.92(d, 2H, J = 8.5 Hz),

5.35(d, 1H, J = 1.5 Hz), 3.98(q, 1H, J = 3.1 Hz), 3.82(dd, 1H, J = 9.5 Hz), 3.64(m,

1H), 3.43(t, 1H, J = 19.0 Hz), 2.27(s, 3H), 1.21(d, 3H, J = 6.2 Hz)

ESI-LRMS: Calcd for C₁₃H₁₈O₅Na (M+Na⁺) 277.10, found 277.11

JOURNAL OF CARBOHYDRATE CHEMISTRY

Acknowledgements

We sincerely thank the analytic center of East China Normal University for data measurements.

We appreciate Ms Chunjuan Shi, Mr Wei Liu, Mr Simin Zhou, Mr Haoqiang Qi, and Mr Wenshuai

Si for helpful discussion. The project was supported by “DAXIA” Science Research Foundation of

East China Normal University (KY2005–017), Shanghai Pujiang Program (05PJ14315), Shanghai

Rising-Star Program (06QA14018), the Natural Science Foundation of Shanghai (11ZR1410400)

and large instruments Open Foundation of East China Normal University (2012–92, 20151043

&20162015).

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