Total synthesis of phenylpropanoid glycoside osmanthuside-B6 facilitated by double isomerisation of glucose-rhamnose orthoesters

Article abstract of DOI:10.1039/c7ob00198c

A convenient synthesis of phenylpropanoid glycoside osmanthuside-B₆ is disclosed. The key steps involved regioselective coumaroylation and rhamnosylation of unprotected phenylethyl-β-d-glucopyranoside to give 2- and 3-O-rhamnosyl orthoester glucopyranosides. Rearrangement of these orthoesters followed by selective removal of their acetyl and allyl groups gave osmanthuside-B₆ in 22% overall yield. The rearrangement involved a newly discovered glucose-rhamnose orthoester double isomerization process that has the potential to provide a convenient access to many complex phenylpropanoid glycosides. The synthetic route developed is envisioned to serve as a model for the preparation of phenylpropanoid glucosides having a (substituted) cinnamoyl moiety at O-6 and a saccharide moiety at O-3.

Full text of DOI:10.1039/c7ob00198c

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Takeharu Haino et al.
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PAPER
Total synthesis of phenylpropanoid glycoside osmanthuside‐B6
facilitated by double isomerisation of glucose‐rhamnose
orthoesters
Duc Thinh Khong, Zaher M.A. Judeh*
,Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A convenient synthesis of phenylpropanoid glycoside osmanthuside‐B6 is disclosed. The key steps involved regioselective
coumaroylation and rhamnosylation of unprotected phenylethyl‐β‐D‐glucopyranoside to give 2‐ and 3‐O‐rhamnosyl
www.rsc.org/
orthoester glucopyranosides. Rearrangement of these orthoesters followed by selective removal of their acetyl and allyl
groups gave osmanthuside‐B6 in 22% overall yield. The rearrangemet involved a newly discovered glucose‐rhamnose
orthoester double isomerization process that has potential to provide
a convenient access to many complex
phenylpropanoid glycosides. The synthetic route developed is envisioned to serve as a model for the preparation of
phenylpropanoid glucosides having a (substituted) cinnamoyl moiety at O‐6 and a saccharide moiety at O‐3.
The traditional synthesis of PhGs is heavily dependent on
protection/deprotection approaches that are mostly cumbersome,
Introduction
Phenylpropanoid glycosides (PhGs) are natural products widely
distributed in the plant kingdom and show many important
long and low yielding.16‐22 Additionally, chemical incompatibilities
between the cinnamoyl moieties and the protecting
groups/deprotecting reagents are major synthetic challenges to
overcome.23 We have recently developed very convenient and short
approach for the synthesis of simple PhGs acylated at O‐6 and
reported the synthesis of calceolarioside‐B, eutigoside‐A,
medicinal properties.1,2 Their core structure, 2‐phenylethyl‐β‐
D‐
glucoside, is acylated with a (substituted) cinnamoyl moiety and
may contain additional saccharide bonded to the glucoside core
through glycosidic bonds. Osmanthuside‐B6 1,3 isoacteoside 2,4
isomartynoside 35, leucosceptoside‐A 46, and several others,1,2
represent a subclass of PhGs with a substituted cinnamoyl moiety at
O‐6 and a rhamnosyl moiety at O‐3 of the glucoside (Figure 1).
grayanoside‐A
and
several
PhG
analogues
without
protection/deprotection steps.24,25 Given our experience,24‐27 we
decided to explore the synthesis of osmanthuside‐B6 1 as a model
for the preparation of over 50 complex PhGs including PhGs 2‐4
(Figure 1).1 The similarities between the structures of PhGs 1‐4
suggested that a common synthetic approach that allows for
selective introduction of building blocks 2‐phenylethyls (pink),
substituted cinnamoyls (red) and rhamnosyl (blue) on the glucose
unit is desirable. It would be even more desirable if
protection/deprotection steps are avoided or minimized to simplify
the synthesis. The only reported attempt at the total synthesis of
osmanthuside‐B6 1 relied on protection/deprotection approach and
gave 2‐O‐acetyl osmanthuside‐B6 since the final deacetylation step
at O‐2 failed to afford osmanthuside‐B6 1.28
These
PhGs
show
α‐glucosidase,7
aldol
reductase,8,9
antioxidation,10‐13 antibacterial14 and hepatoprotective15 activities.
Herein, we report the total synthesis of osmanthuside‐B6 1 as a
model for the preparation of over 50 complex PhGs (including PhGs
2‐4) having a (substituted) cinnamoyl moiety at O‐6 and a
rhamnosyl moiety at O‐3. We also report on a newly discovered
glucose‐rhamnose orthoester double isomerisation process.
Figure 1. Phenylpropanoid glucosides
Results and Discussion
Our proposed synthetic route for osmanthuside‐B6 1 features three
sequential key steps as outlined in Figure 2. i) 1,2‐Trans‐β‐
glycosylation of
D‐glucose peracetate 5 (R = acetyl = Ac) with 2‐(4‐
allyloxyphenyl)ethanol
6
assisted by neighbouring group
participation. ii) Direct regioselective O‐6 acylation of the
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unprotected glucoside (R = H) with 4‐allyloxycoumaroyl chloride 7.
iii) Direct 1,2‐trans‐α‐glycosylation between the unprotected
glucoside (R = H) and rhamnosyl donor 8.
glucopyranoside 10 was recovered (Table 1, entry 4). By increasing
the amount of rhamnosyl chloride 12 to 3 equiv., the glycosylation
proceeded faster to give better yields of both 3‐orthoester 13 (42%)
and 2‐orthoester 14 (41%) with just 10% recovered starting
glucopyranoside 10 (Table 1, entry 5). Switching Ag2CO3 with Ag2O30
has no positive impact on the selectivity or yield (Table 1, entry 5 vs
entry 6). However, replacing CH2Cl2 with MeCN favoured the
formation of 3‐orthoester 13 (31 % yield) over 2‐orthoester 14 (20%
yield) albeit 39% of the starting glucopyranoside 10 was recovered
(Table 1, entry 7). Fortunately, catalytic amount of 2‐aminoethyl
diphenylborinate30 achieved complete conversion and the reaction
afforded 3‐orthoester 13 in 55% yield and 2‐orthoester 14 in 36%
yield in just 3‐4 h (Table 1, entry 8). Heating was necessary, as the
reaction under room temperature was very sluggish. To ascertain
the positions of the rhamnosyl moieties on orthoesters 13 and 14,
we prepared their acylated derivatives 15 and 16 (Scheme 2) and
performed COSY experiments (See supporting information).
Table 1. Koenigs‐Knorr glycosylation of glucopyranoside 10 using
rhamnosyl halides 11 and 12
O
Cl
ii) direct regioselective
AllO
acylation at primary hydroxyl
group (R = H)
7
OR

-
i) 1,2-trans-
HO
O
glycosylation
(R = Ac)
RO
RO
OR
OAll
OR
iii) direct 1,2-trans-
-glycosylation
(R = H)
6

5
X
O
deprotection of the allyl
and acetyl groups
AcO
AcO
OAc
Osmanthuside-B6 1
8
Figure 2. Proposed route for synthesis of osmanthuside‐B6 1
The 1,2‐trans‐β‐glycosylation of D‐glucose peracetate 5 with 2‐(4‐
allyloxyphenyl)ethanol 618 followed by deacetylation using NaOMe
gave 2‐(4‐allyloxyphenyl)ethyl‐β‐D‐glucopyranoside 9 in 82% overall
yield. Direct regioselective Me2SnCl2‐catalyzed O‐6 acylation of
glucopyranoside
9 with 4‐allyloxycoumaroyl chloride 7 gave
glucopyranoside 10 in 86% yield (Scheme 1).24,25
HO
AcO
AcO
AcO
HO
HO
O
O
OAll
6
OAc
O
HO
O
OAc
OH
a, b
OAll
5
9
82 %
O
13
14
Recovered
10 (%)a
81
Entry
Conditions
(%)a
n.d.
(%)a
12
Cl
O
1
2
1.2 equiv. 11, Ag2CO3, CH2Cl2, rt, 16 h
1.2 equiv. 11, Ag2CO3, s‐collidine, CH2Cl2, rt,
16 h
7
AllO
O
AllO
HO
HO
O
c
n.d.
10
73
OH
OAll
3
4
5
6
7
3 equiv. 11, Ag2CO3, CH2Cl2, rt, 8 h
1.2 equiv. 12, Ag2CO3, CH2Cl2, reflux, 18 h
3 equiv. 12, Ag2CO3, CH2Cl2, reflux, 6 h
3 equiv. 12, Ag2O, CH2Cl2, reflux, 6 h
1.2 equiv. 12, Ag2O, MeCN, 60 C, 8 h
1.2 equiv. 12, Ag2O, 2‐aminoethyl
diphenylborinate, MeCN, 60 oC, 3 h
18
33
41
39
31
29
34
42
44
20
45
31
12
10
39
10
86 %
Reagents and conditions: a) 6, BF3.OEt2, CH2Cl2, MS 4Å, rt, 12 h; b) NaOMe, MeOH, rt , 1 h;
7
c) , Me2SnCl2 THF, DIPEA, rt ,12 h
Scheme 1. Synthesis of glucopyranoside 10
8
55
36
n.d.
a: isolated yields. n.d.: not detected
Initial direct glycosylation attempts between glucopyranoside 10
and 2,3,4‐tri‐O‐acetyl‐α‐L‐rhamnopyranosyl trichloroacetimidate
We anticipated that the rearrangement31 of 3‐orthoester 13 to 3‐O‐
rhamnosyl glucopyranoside 17 followed by removal of its allyl and
acetyl groups would furnish osmanthuside‐B6 1 (Scheme 2).
However, the rearrangement of 3‐orthoesters 13 using TMSOTf or
BF3.OEt2 in CH2Cl2 at ‐78 C afforded a mixture of glucopyranosides
10 (~10 yield), 17 (~10% yield), 18 (~13% yield) and O,O‐
dirhamnosyl glucopyranosides (~32% yield). The formation of
glucopyranoside 18 and O,O‐dirhamnosyl glucopyranosides was
surprising as it involved not just the usual orthoester isomerisation,
which gave the expected glucopyranoside 17, but also a new double
isomerization resulting in a rhamnosyl moiety shift from O‐3 to O‐2
of glucose.32 The exact positions of the rhamnosyl moieties on
glucopyranosides 17 and 18 were identified by COSY experiments
on their fully acetylated 3‐O‐rhamnosyl glucopyranoside 19 and 2‐
O‐rhamnosyl glucopyranoside 20 (See supporting information). To
prevent the shift of the rhamnosyl moiety, 3‐orthoesters 13 was
acetylated to 3‐orthoester 15 which upon rearrangement under the
using the standard protocol of TMSOTf in CH2Cl2 at ‐78 C gave a
complex mixture of compounds due to uncontrolled glycosylation.
To improve the glycosylation selectivity, we tested the less reactive
rhamnosyl bromide 11 and rhamnosyl chloride 12 as donors (Table
1). Both donors gave a mixture of stable 3‐orthoester 13 and 2‐
orthoester 14 (Table 1). No 4‐orthoester was formed due to the
lower reactivity of the 4‐OH in comparison to the 3‐OH and 2‐OH.1
Glycosylation using 1.2 equiv. of rhamnosyl bromide 1129 was
sluggish (with/out s‐collidine scavenger) and gave only 10‐12% yield
of 2‐orthoester 14 as majority of the starting glucopyranoside 10
was recovered unchanged (Table 1, entries 1‐2). When 3 equiv. of
rhamnosyl bromide 11 were used, the reaction gave 3‐orthoester
13 in 18% yield and 2‐orthoester 14 in 29% yield (Table 1, entry 3).
However, glycosylation with 1.2 equiv. of rhamnosyl chloride 12,
which is more stable but less reactive in comparison to rhamnosyl
bromide 11, resulted in better yields of both 3‐orthoester 13 (34%)
and 2‐orthoester 14 (33%) albeit 31% of the starting
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same conditions afforded the expected 3‐O‐rhamnosyl rhamnosyl glucopyranoside 21 using Pd‐C/p‐TsOH afforded
glucopyranoside 19 in 86% yield (Scheme 2). This proved the osmanthuside‐B6 1 in 71% yield (Scheme 2). The 1H NMR, 13C NMR,
participation of the free OH of glucopyranosides 10 in formation of and specific optical rotation data of the synthesized osmanthuside‐
glucopyranoside 18 and O,O‐dirhamnosyl glucopyranosides. B6 1 are in agreement with literature values.3
Likewise, under the same conditions, rearrangement of 2‐
Double isomerization involving glucose‐rhamnose 2‐orthoesters
such as orthoester 14 has not been reported before.32 Though no
orthoester 14 gave a mixture of glucopyranosides 10 (10% yield), 17
(6% yield), 18 (8% yield) and O,O‐dirhamnosyl glucopyranosides
special investigation of this isomerization was performed yet; a
proposed mechanism for the formation of glucopyranosides 17 and
(37% yield). Interestingly, the rearrangement of 2‐orthoester 14
using TMSOTf in MeCN at ‐20 C improved the selectivity and
18 is depicted in Scheme 3. Reaction of 2‐orthoester 14 with
effectively afforded the desired 3‐O‐rhamnosyl glucopyranoside 17
TMSOTf resulted in selective bond breakage and formation of
acyloxonium cations 22 and 23.34 Rearrangement via the six‐
in 52% yield along with 2‐O‐rhamnosyl glucopyranoside 18 (33%
yield) and glucopyranoside 10 (11% yield).
membered ring transition states 24 and 25 led to the formation of
Next,
chemoselective
deacetylation
of
3‐O‐rhamnosyl glucopyranosides 17 and 18, respectively. However, a more likely
33
glucopyranoside 17 using Mg(OMe)2 successfully afforded 3‐O‐ transition state such as 26 is responsible for the formation of higher
rhamnosyl glucopyranoside 21 in 73% yield (Scheme 2). However, yield of glucopyranoside 17 as it involves intramolecular attack of
under the same conditions, complete deacetylation of 3‐O‐ the nucleophilic O‐3, with the least steric hindrance, on the
rhamnosyl glucopyranoside 19 was unsuccessful probably because electrophilic C‐1 of the rhamnosyl moiety and cleavage of the C‐O‐2
the glucoside acetyl groups experience strong neighbouring steric bond. Interestingly, such double isomerization to give
hindrance.28 Nevertheless, complete and chemoselective glucopyranosides 17 did not occur with similar partially protected
deacetylation of 3‐O‐rhamnosyl glucopyranoside 19 was achieved 1,2‐orthoesters of glucose29 and mannose35 suggesting the double
19
using MeNH2 to give 3‐O‐rhamnosyl glucopyranoside 21 in 67% isomerization is a substrate‐dependent process. The mechanism of
yield (Scheme 2). Finally, removal of the allyl groups of 3‐O‐ this double isomerization and application is under investigation.
Scheme 2. Final steps in the total synthesis of osmanthuside‐B6 1
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OR2
OR2
OR2
O
O
O
O
HO
HO
HO
HO
OR1
OR1
HO
HO
OR1
O
O
TMS+
TMS
O
O
O
O
AcO
AcO
O
AcO
AcO
AcO
OTf
O
O
AcO
OTf
22
OAc
24
18
OR2
OR2
O
O
OR2
HO
HO
OR1
O
O
HO
O
HO
OR2
OR1
OR1
O
TMSOTf
O
OH
TMS
O
OH
HO
O
OH
TMS+
OR1
O
O
O
O
AcO
O
O
AcO
O
AcO
O
OTf
AcO
AcO
O
O
OAc
14
AcO
OTf
25
23
OAc
17
AcO
OR2
3
HO
HO
OR1
2
O
R1 =
1
HO
OAll
O
O
OTf
O
R2 =
OAc
26
OAll
AcO
Scheme 3. A proposed mechanism for the formation of glucopyranosides 17 and 18 through isomerization of glucopyranoside 14
The double isomerization process is a powerful method to
isomerize disaccharide orthoesters to obtain a desired substitution
Experimental Section
Chemical reagents were purchased from Sigma‐Aldrich or Alfa Aesar
and were used as received without further purification. CH2Cl2 was
distilled over CaH2 and stored over activated MS 3ꢀ bead. TMSOTf
was distilled before use. MeCN was dried by storing over activated
MS 3ꢀ bead. 1H NMR spectra were recorded at 300 MHz on a
Bruker Avance DPX 300. 13C NMR spectra were recorded at 75.47
MHz on a Bruker Avance DPX 300. HRMS were recorded on Qstar XL
MS/MS system Analytical TLC was performed using Merck 60 F254
precoated silica gel plates (0.2‐mm thickness) and visualized using
UV radiation (254 nm). Flash chromatography was performed using
Merck silica gel 60 (230–400 mesh). Optical rotation values were
measured on JASCO P‐1020 polarimeter.
pattern that is otherwise difficult to obtain through direct
glycosylation on unprotected disaccharides.
Conclusion
Synthesis of osmanthuside‐B6 1 was achieved in seven steps in 22%
overall yield without extensive protection/deprotection steps.
Glycosylation of glucopyranoside 10 with rhamnosyl chloride 12
gave a mixture of 2‐ and 3‐O‐orthoesters 13 and 14 that were
converted conveniently through simple isomerization to
osmanthuside‐B6 1. The newly discovered double isomerization
involved rearrangement of the rhamnosyl orthoester moiety and
shift from O‐2 to O‐3. This isomerization process is envisioned to
provide access to complex phenylpropanoid glycosides that are
difficult to prepare through direct glycosylation. The mechanism of
the newly discovered glucose‐rhamnose double isomerization and
its application is currently under investigation. Based on this
approach, synthesis of complex phenylpropanoid glucosides such as
isoacteoside 2, martynoside 3 and leucosceptoside‐A 4 and others is
within reach.
[2‐(4‐Allyloxyphenyl)]ethyl β‐D‐glucopyranoside 9:
To a stirred solution of glucose peracetate 5 (3 g, 7.7 mmol) in dry
CH2Cl2 (50 mL) was added 2‐(4‐allyloxyphenyl) ethanol 6 (600 mg,
3.5 mmol) under N2 atmosphere at room temperature. MS 4Å (3 g)
was then added, and the reaction mixture stirred for 30 min before
drop‐wise addition of BF3.OEt2 (0.43 mL, 3.6 mmol). The reaction
was stirred ~15 h until the complete consumption of 2‐(4‐
allyloxyphenyl) ethanol 6 as shown by TLC. Additional BF3.OEt2 (0.2
mL) was then added and the reaction was stirred for additional 2 h.
The reaction was then quenched with saturated NaHCO3, diluted
with CH2Cl2 (50 mL), and filtered through a pad of Celite®. The
biphasic filtrate was separated and the aqueous phase was further
extracted with CH2Cl2 (30 mL x 2). The combined organic phases
were washed with brine, dried over MgSO4, filtered and evaporated
to dryness. The crude residue obtained was redissolved in MeOH
Acknowledgment
We thank Nanyang Technological University Tier 1 grant
(Call2/2016) for financial support.
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(25 mL), NaOMe (50 mg) was added and the reaction mixture elution with EtOAc : hexane = 1 : 2 to EtOAc : hexane = 2 : 1) to give
stirred for 1 h before the addition of Amberlite IR 120. The reaction 3‐orthoester 13 (Rf = 0.5 in EtOAc : hexane = 1 : 1) (250 mg, 55%
mixture was then stirred for 3 h, filtered and evaporated. The crude yield) and 2‐orthoester 14 (Rf = 0.2 in EtOAc : hexane = 1 : 1) (163
residue was purified by flash column chromatography (MeOH: mg, 36% yield).
CH2Cl2 = 1 : 20) to give the glycosylated product 9 (0.97 g, 82% yield)
as amorphous solid. ꢁꢂꢃꢄꢅꢆ ꢇ 34 ꢈꢉ 3.00, ꢊꢋꢌꢍꢎ. 1H NMR (MeOD)
δ: 2.75 (t, J= 7.35 Hz, 2H), 3.07 (t, J= 8.25 Hz, 1H), 3.15‐3.24 (m, 3H), 3,4‐di‐O‐Acetyl‐α‐L‐rhamnopyranose
1,2‐[2‐(4‐
β‐D‐
3.52‐3.64 (m, 2H), 3.73‐3.77 (m, 1H), 3.90‐3.98 (m, 1H), 4.18 (d, J= allyloxylphenyl)ethyl
7.8 Hz, 1H), 4.39 (dt, J= 1.5, 5.4 Hz, 2H), 4.50 (s, 3H, OH), 5.12 (dd, J= glucopyranosid‐3‐yl orthoacetate] 13:
1.5, 10.5 Hz, 1H), 5.26 (dd, J= 1.8, 17.4 Hz, 1H), 6.72 (d, J= 8.7 Hz,
6‐O‐(E)‐4‐allyloxycoumaryl
2H), 7.05 (d, J= 8.4 Hz, 2H). 13C NMR (MeOD) δ: 37.8, 64.2, 71.3,
73.1, 73.4, 76.6, 79.5, 79.6, 105.9, 117.2, 118.8, 132.5, 133.7, 136.6, ꢁꢂꢃꢅꢄꢆ ꢇ 33.5 ꢈꢉ 2.74, ꢏꢍꢅꢏꢐꢅꢎ.1H NMR (CDCl3) δ: 1.17 (d, J= 5,1 Hz,
160.1. HRMS (ESI+): m/z [M + H]+ calcd for C17H25O7: 341.1600; 3H, Rha‐H6), 1.79 (s, 3H, CH3), 1.99 (s, 3H, Ac), 2.01 (s, 3H, ‐Ac), 2.83
found: 341.1603.
(t, J= 7.1 Hz, 2H, ‐CH2CH2‐Ar), 3.30‐3.36 (m, 2H, Glu‐H2, ‐OH), 3.38‐
3.51 (m, 4H, Glu‐H5, Glu‐H4, Glu‐H3, Rha‐H5), 3.61‐3.68 (m, 1H, ‐
CH2aCH2‐Ar), 3.95‐4.03 (m, 1H, ‐CH2bCH2‐Ar), 4.25 (d, J= 7.8 Hz, Glu‐
β‐D‐ H1), 4.38‐4.41 (m, 4H, Glu‐H6, ‐CH2‐CH=CH2), 4.49‐4.51 (m, 2H, ‐
CH2‐CH=CH2), 4.61‐4.64 (m, 1H, Rha‐H2), 4.88‐5.01 (m, 1H, Rha‐H4),
5.02‐5.05 (m, 1H, Rha‐H3), 5.19‐5.41 (m, 4H, 2 x ‐CH2‐CH=CH2), 5.44
(d, J= 2.1 Hz, Rha‐H1), 5.90‐6.05 (m, 2H, ‐CH2‐CH=CH2), 6.25 (d, J=
[2‐(4‐Allyloxyphenyl)]ethyl
glucopyranoside 10:
6‐Ο‐(E)‐4‐allyloxycoumaryl
To a solution of 2‐(4‐allyloxyphenyl)ethyl β‐D‐glucopyranoside 9 15.9 Hz, 1H, ArCH=CHCOO‐), 6.72 (d, J= 8.7 Hz, 2H, ArH), 6.83 (d, J=
(340 mg, 1 mmol) in THF (10 mL) was added Me2SnCl2 (11 mg, 0.05 8.7 Hz, 2H, ArH), 7.04 (d, J= 8.4 Hz, 2H, ArH), 7.37 (d, J= 8.7 Hz, 2H,
mmol), 4‐allyloxycoumaryl chloride 7 (330 mg, 1.5 mmol) and DIPEA ArH), 7.58 (d, J= 15.9 Hz, 1H, ArCH=CHCOO‐). 13C NMR (CDCl3) δ:
(0.35 mL, 2 mmol). The reaction was stirred for 12 h, diluted with DI 17.4, 20.6, 20.7, 25.9, 35.2, 63.3, 68.7, 68.8, 68.9, 69.0, 70.0, 70.1,
H2O (15 mL), and extracted with EtOAc (15 mL x 3). The organic 71.1, 72.1, 73.8, 76.9, 79.7, 97.0, 102.8, 114.7, 115.0, 115.1, 117.5,
phases were washed with brine, dried over MgSO4, filtered and 118.0, 124.1, 127.2, 129.81, 129.84, 130.4, 132.8, 133.4, 144.9,
evaporated to dryness. The crude product was purified by flash 157.1, 160.4, 167.3, 169.8, 170.4. HRMS (ESI+): m/z [M + H]+ calcd
column chromatography (EtOAc: CH2Cl2 = 3 : 1) to give product 10 for C41H51O16: 799.3177; found: 799.3171.
(0.47 g, 91% yield) as amorphous solid. ꢁꢂꢃꢅꢄꢆ ꢇ 41 ꢈꢉ 3.20, ꢏꢍꢅꢏꢐꢅꢎ.
1H NMR (CDCl3) δ: 2.78 (t, J= 7.5 Hz, 2H), 3.31‐3.47 (m, 3H), 3.51 (q,
J= 8.7 Hz, 1H), 3.63 (q, J= 9.3 Hz, 1H), 4.02 (q, J= 9.6 Hz, 1H), 4.25 (d, 3,4‐di‐O‐Acetyl‐α‐L‐rhamnopyranose
1,2‐[2‐(4‐
β‐D‐
J= 7.8 Hz, 1H), 4.31‐4.35 (m, 1H), 4.38 (d, J= 5.4 Hz, 1H), 4.47 (d, J= allyloxylphenyl)ethyl
5.1 Hz, 1H), 4.52‐4.57 (m, 1H), 5.89‐6.03 (m, 1H), 6.26 (d, J= 15.9 Hz, glucopyranosid‐2‐yl orthoacetate] 14:
1H), 6.72 (d, J= 8.4 Hz, 2H), 6.81 (d, J= 8.7 Hz, 2H), 7.02 (d, J= 8.7 Hz,
6‐O‐(E)‐4‐allyloxycoumaryl
2H), 7.34 (d, J= 8.7 Hz, 2H), 7.58 (d, J= 15.9 Hz, 1H). Acylation at O‐6
was confirmed by the downfield shift of H6 protons of 9 from δ3.74 ꢁꢂꢃꢅꢄꢆ ꢇ 42 ꢈꢉ 2.0, ꢏꢍꢅꢏꢐꢅꢎ.1H NMR (CDCl3) δ: 1.15 (d, J= 6.3 Hz, 3H,
(H6a) and δ3.58 (H6b)36 to δ4.54 (H6a) and δ4.33 (H6b)17 in 10.13C Rha‐H6), 1.68 (s, 3H, CH3), 1.98 (s, 6H, 2 x ‐Ac), 2.79 (t, J= 7.8 Hz, 2H,
NMR (CDCl3) δ: 35.2, 63.3, 68.77, 68.83, 68.9, 70.0, 71.2, 73.6, 74.3, ‐CH2CH2‐Ar), 3.20 (d, J= 2.4 Hz, 1H, OH), 3.32‐3.48 (m, 5H, Glu‐H5,
75.6, 102.9, 114.8, 114.9, 115.1, 117.6, 118.1, 127.0, 129.9, 130.0, Glu‐H4, Glu‐H3, Glu‐H2 Rha‐H5), 3.56‐3.65 (m, 1H, ‐CH2aCH2‐Ar),
132.7, 133.4, 145.8, 157.2, 160.6, 167.9. HRMS (ESI+): m/z [M + H]+ 3.93‐4.02 (m, 1H, ‐CH2bCH2‐Ar), 4.25‐4.35 (m, 2H, Glu‐H6a, Glu‐H1),
calcd for C29H35O9: 527.2281; found: 527.2294.
4.42 (dt, J= 1.35, 5.4 Hz, ‐CH2‐CH=CH2), 4.49‐4.53 (m, 3H, ‐CH2‐
CH=CH2, Glu‐H6b), 4.64 (dd, J= 2.4, 3.9 Hz, Rha‐H2), 4.97 (t, J= 9.6
Hz, 1H, Rha‐H4), 5.08 (dd, J= 3.9, 9.7 Hz, Rha‐H3), 5.18‐5.38 (m, 5H,
Glycosylation of 2,3,4‐tri‐O‐acetyl‐α‐L‐rhamnopyranosyl rhamnosyl Rha‐H1, 2 x –CH2‐CH=CH2), 5.93‐6.04 (m, 2H, 2 x –CH2‐CH=CH2),
chloride
12
with
2‐(4‐allyloxyphenyl)ethyl
6‐Ο‐(E)‐4‐ 6.29 (d, J= 15.9 Hz, 1H, ArCH=CHCOO‐), 6.75 (d, J= 8.7 Hz, 2H, ArH),
6.84 (d, J= 8.7 Hz, 2H, ArH), 7.07 (d, J= 8.7 Hz, 2H, ArH), 7.38 (d, J=
8.7 Hz, 2H, ArH), 7.60 (d, J= 15.9 Hz, 1H, ArCH=CHCOO‐). 13C NMR
(CDCl3) δ: 17.4, 20.75, 20.78, 24.8, 35.3, 63.1, 68.8, 68.9, 69.2, 70.0,
allyloxycoumaryl β‐D‐glucopyranoside 10 :
A mixture of 2‐(4‐allyloxyphenyl)ethyl 6‐Ο‐(E)‐4‐allyloxycoumaryl β‐ 70.3, 71.2, 73.7, 75.7, 76.0, 76.3, 97.0, 101.8, 114.7, 114.9, 115.1,
D‐glucopyranoside 10 (300 mg, 0.57 mmol), 2,3,4‐tri‐O‐acetyl‐α‐L‐ 117.5, 118.1, 124.1, 127.1, 129.9, 130.5, 132.7, 133.4, 145.5, 157.2,
rhamnopyranosyl chloride 12 (210 mg, 0.68 mmol), Ag2O (400 mg, 160.6, 167.9, 169.9, 170.4. HRMS (ESI+): m/z [M + H]+ calcd for
1.71 mmol), 2‐aminoethyl diphenylborinate (6.4 mg, 5 mol%), C41H51O16: 799.3177; found: 799.3176.
activated MS 4Å (500 mg) in flame‐dried round bottom flask was
vacuumed and filled with N2. Anhydrous MeCN (5 mL) was then
introduced using a syringe. The reaction was heated at 60 C for 3 h 3,4‐di‐O‐Acetyl‐
α‐L‐rhamnopyranose
1,2‐[2‐(4‐
whereupon TLC analysis shown complete consumption of starting allyloxylphenyl)ethyl 6‐O‐(E)‐4‐allyloxycoumaryl 2,4‐di‐O‐acetyl β‐
material 10. The reaction was filtered through a pad of Celite® and D‐glucopyranosid‐3‐yl orthoacetate] 15
the filtrate was evaporated under reduced pressure. The crude
residue was purified by flash column chromatography (gradient
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3‐orthoester 13 (100 mg, 0.13 mmol) was dissolved in pyridine (0.5 TMSOTf‐catalyzed rearrangement of 2‐orthoester 14:
mL) followed by drop‐wise addition of Ac2O (0.5 mL). The reaction
was stirred at room temperature overnight, followed by co‐
evaporation with toluene to remove excess pyridine and Ac2O. The To a mixture of 2‐orthoester 14 (100 mg, 0.13 mmol), activated MS
crude residue was purified by flash column chromatography (EtOAc: 4Å (200 mg) in round bottom flask under N2 atmosphere was added
hexane = 1 : 3) to afford acetylated 3‐orthoester 15 (108 mg, 95% anhydrous MeCN (10 mL). The mixture was stirred for 30 min. then
yield) as white amorphous solid. ꢁꢂꢃꢅꢄꢆ ꢇ 4.2 ꢈꢉ 3.34, ꢏꢍꢅꢏꢐꢅꢎ.1H cooled down to ‐20 C before addition of TMSOTf (5 μl, 0.025
NMR (CDCl3) δ: 1.14 (d, J= 6 Hz, 3H, Rha‐H6), 1.59 (s, 3H, ‐CH3), 1.92 mmol). The reaction was stirred for at least 1 h whereupon TLC
(s, 3H, ‐Ac), 1.98 (s, 3H, ‐Ac), 2.02 (s, 9H, 3 x ‐Ac), 2.72‐2.77 (m, 2H, ‐ analysis showed complete conversion of the starting material and
CH2CH2‐Ar), 3.39‐3.49 (m, 1H, Rha‐H5), 3.50‐3.58 (m, 1H, ‐CH2aCH2‐ formation of two spots at Rf = 0.6 and 0.2 (EtOAc: hexane = 1 : 1).
Ar), 3.60‐3.67 (m, 1H, Glu‐H5), 3.79 (t, J= 9.15 Hz, 1H, Glu‐H3), 3.93‐ Et3N (20 μl) was then added into the reaction mixture which was
4.02 (m, 1H, ‐CH2bCH2‐Ar), 4.15‐4.30 (m, 2H, Glu‐H6), 4.40‐4.49 (m, stirred for 15 min as it was allowed to warm to room temperature.
6H, 2 x –CH2‐CH=CH2, Glu‐H1, Rha‐H2), 4.72 (t, J= 8.7 Hz , Glu‐H2), The mixture was filtered through a pad of Celite®, the filtrate was
4.84‐4.95 (m, 2H, Glu‐H4, Rha‐H4), 5.08 (dd, J= 3.9, 9.6 Hz, Rha‐H3), evaporated and the crude residue was purified by flash column
5.18‐5.39 (m, 5H, 2 x –CH2‐CH=CH2, Rha‐H1), 5.90‐6.05 (m, 2H, 2 x chromatography (gradient EtOAc: hexane = 1 : 2 to EtOAc : hexane
–CH2CH=CH2‐), 6.25 (d, J= 15.9 Hz, 1H, ArCH=CHCOO‐), 6.75 (d, J= = 2 : 1) to afford 3‐O‐rhamnosyl glucopyranoside 17 and 2‐
8.7 Hz, 2H, ArH), 6.84 (d, J= 8.7 Hz, 2H, ArH), 7.02 (d, J= 8.7 Hz, 2H, rhamnosylate 18 in 52% and 33% respectively as white amorphous
ArH), 7.39 (d, J= 8.7 Hz, 2H, ArH), 7.57 (d, J= 15.9 Hz, 1H, solid.
ArCH=CHCOO‐). From H‐H COSY, proton Glu‐H3 at δ3.79 showed a
cross peak with acetylated Glu‐H2 at δ4.72 and acetylated Glu‐H4 at
δ4.84‐4.95 thus confirming the formation of orthoester bond at O‐3 [2‐(4‐Allyloxyphenyl)ethyl]
3‐(2,3,4‐tri‐O‐acetyl
α‐L‐
of glucose unit.13C NMR (CDCl3) δ: 17.5, 20.76, 20.80, 20.9, 21.0, rhamnopyranosyl) 6‐Ο‐(E)‐4‐allyloxycoumaryl β‐D‐glucopyranoside
25.8, 35.1, 62.5, 68.8, 68.9, 69.3, 70.3, 70.7, 71.8, 72.4, 74.2, 96.9, 17:
100.6, 114.6, 115.0, 115.1, 117.6, 118.1, 124.7, 127.1, 129.89,
129.92, 130.8, 132.8, 133.4, 145.2, 157.1, 160.5, 166.9, 169.4, 169.8,
170.2. HRMS (ESI+): m/z [M + H]+ calcd for C45H55O18: 883.3388; ꢁꢂꢃꢅꢄꢆ ꢇ 71 ꢈꢉ 2.12, ꢏꢍꢅꢏꢐꢅꢎ.1H NMR (CDCl3) δ: 1.14 (d, J= 6.3 Hz,
found: 883.3391.
3H, Rha‐H6), 1.91 (s, 3H, ‐Ac), 1.97 (s, 3H, ‐Ac), 2.07 (s, 3H, ‐Ac),
2.80 (t, J= 7.7 Hz, 2H, ‐CH2CH2‐Ar), 3.35‐3.60 (m, 5H, ‐CH2aCH2‐Ar,
Glu‐H5, Glu‐H4, Glu‐H3, Glu‐H2), 3.95‐4.05 (m, 1H, ‐CH2bCH2‐Ar),
1,2‐[2‐(4‐ 4.10‐4.19 (m, 2H, Glu‐H1, Rha‐H5), 4.25‐4.31 (m, 1H, Glu‐H6a),
3,4‐di‐O‐Acetyl‐
α‐L‐rhamnopyranose
allyloxylphenyl)ethyl 6‐O‐(E)‐4‐allyloxycoumaryl 3,4‐di‐O‐acetyl β‐ 4.40‐4.55 (m, 4H, 2 x ‐CH2‐CH=CH2), 4.52‐4.59 (m, 1H, Glu‐H6b),
D‐glucopyranosid‐2‐yl orthoacetate] 16
4.95‐5.05 (m, 1H, Rha‐H4), 5.10 (d, J= 1.2 Hz, 1H, Rha‐H1), 5.21‐5.35
(m, 6H, 2 x ‐CH2‐CH=CH2,, Rha‐H2, Rha‐H3), 5.90‐6.05 (m, 2H, 2 x ‐
CH2‐CH=CH2), 6.31 (d, J= 15.9 Hz, 1H, ArCH=CHCOO‐), 6.75 (d, J= 8.7
2‐orthoester 14 (100 mg, 0.13 mmol) was dissolved in pyridine (0.5 Hz, 2H, ArH), 6.84 (d, J= 8.7 Hz, 2H, ArH), 7.04 (d, J= 8.7 Hz, 2H, ArH),
mL) followed by drop‐wise addition of Ac2O (0.5 mL). The reaction 7.40 (d, J= 8.7 Hz, 2H, ArH), 7.63 (d, J= 15.9 Hz, 1H, ArCH=CHCOO‐).
was stirred at room temperature overnight then co‐evaporated 13C NMR (CDCl3) δ: 17.4, 20.77, 20.85, 21.0, 35.2, 63.1, 66.9, 68.6,
with toluene to remove excess pyridine and Ac2O. The crude 68.8, 68.85, 69.1, 69.8, 71.05, 71.14, 74.0, 74.4, 82.2, 98.4, 103.0,
residue was purified by flash column chromatography (EtOAc: 114.8, 115.1, 117.6, 118.1, 127.1, 129.8, 130.0, 130.5, 132.7, 133.4,
hexane = 1 : 3) to afford the fully acetylated compound 16 (92 mg, 145.8, 157.2, 160.6, 168.1, 170.1, 170.2, 170.3. HRMS (ESI+): m/z
81% yield) as white amorphous solid. 1H NMR (CDCl3) δ: 1.13 (d, J= [M + H]+ calcd for C41H51O16: 799.3177; found: 799.3146.
6.3 Hz, 3H, Rha‐H6), 1.60 (s, 3H, ‐CH3), 1.20 (s, 12 H, 4 x ‐Ac), 2.73‐
2.82 (m, 2H, ‐CH2CH2‐Ar), 3.37 (dd, J= 9.3, 6.15 Hz, 1H, Rha‐H5),
3.60‐3.69 (m, 2H, ‐CH2aCH2‐Ar, Glu‐H5), 3.77 (t, J= 8.25 Hz, Glu‐H2), [2‐(4‐Allyloxyphenyl)]ethyl
2‐(2,3,4‐tri‐O‐acetyl
α‐L‐
3.91‐3.99 (m, 1H, ‐CH2bCH2‐Ar), 4.21‐4.24 (m, 2H, Glu‐H6), 4.34 (d, rhamnopyranosyl) 6‐Ο‐(E)‐4‐allyloxycoumaryl β‐D‐glucopyranoside
J= 7.5 Hz, Glu‐H1), 4.42 (dt, J= 1.5, 5.1 Hz, 2H,–CH2‐CH=CH2), 4.47‐ 18:
5.52 (m, 3H, –CH2‐CH=CH2, Rha‐H2), 4.89‐5.09 (m, 5H, Glu‐H3, Glu‐
H4, Rha‐H1, Rha‐H3, Rha‐H4), 5.17‐5.39 (m, 4H, 2 x –CH2‐CH=CH2),
1
5.91‐6.05 (m, 2H, 2 x –CH2CH=CH2‐), 6.25 (d, J= 15.9 Hz, 1H, ꢁꢂꢃꢅꢄꢆ ꢇ 42 ꢉ 5.32, ꢏꢍꢅꢏꢐꢅ . H NMR (CDCl3) δ: 1.13 (d, J= 6 Hz, 3H,
ArCH=CHCOO‐), 6.76 (d, J= 8.7 Hz, 2H, ArH), 6.84 (d, J= 9 Hz, 2H, Rha‐H6), 1.96 (s, 3H, ‐COCH3), 1.99 (s, 3H, ‐COCH3), 2.10 (s, 3H, ‐
ArH), 7.09 (d, J= 8.7 Hz, 2H, ArH), 7.38 (d, J= 9 Hz, 2H, ArH), 7.57 (d, COCH3), 2.86 (t, J= 7.95 Hz, 2H, ‐CH2CH2‐Ar), 3.30‐3.45 (m, 3H), 3.52
J= 15.9 Hz, 1H, ArCH=CHCOO‐). From H‐H COSY, proton Glu‐H2 at (t, J= 8.4 Hz, 1H), 3.60‐3.71 (m, 3H), 3.98‐4.08 (m, 1H, ‐CH2bCH2‐Ar),
δ3.77 showed a cross peaked with Glu‐H1 at δ4.34 and acetylated 4.21‐4.30 (m, 2H, Glu‐H6), 4.39 (d, J= 7.8 Hz, 1H, Glu‐H1), 4.49 (m,
Glu‐H3 at δ4.89‐5.09 thus confirming the formation of orthoester 4H, 2 x ‐CH2‐CH=CH2), 4.64 (dd, J= 3.6, 12.3 Hz, 1H), 5.03 (t, J= 9.6 Hz,
bond at O‐2 of glucose unit. 13C NMR (CDCl3) δ: 17.5, 20.7, 20.78, 1H), 5.22‐5.41 (m, 7H), 5.94‐6.06 (m, 2H, 2 x ‐CH2‐CH=CH2), 6.31 (d,
20.82, 20.9, 25.5, 35.3, 62.3, 68.8, 68.9, 69.0, 69.1, 70.0, 70.4, 71.2, J= 15.9 Hz, 1H, ArCH=CHCOO‐), 6.79 (d, J= 8.7 Hz, 2H, ArH), 6.87 (d,
71.7, 73.0, 73.9, 76.2, 97.3, 102.2, 114.6, 114.7, 114.9, 115.1, 117.6, J= 8.7 Hz, 2H, ArH), 7.09 (d, J= 8.7 Hz, 2H, ArH), 7.41 (d, J= 8.7 Hz, 2H,
118.1, 123.7, 127.1, 129.89, 129.92, 130.3, 132.7, 133.4, 145.2, ArH), 7.64 (d, J= 15.9 Hz, 1H, ArCH=CHCOO‐). 13C NMR (CDCl3) δ:
ꢈ
ꢎ
157.2, 160.5, 166.8, 169.7, 169.8, 170.1, 170.3.
17.3, 20.83, 20.84, 21.0, 35.3, 63.1, 66.4, 68.8, 68.9, 69.4, 69.8, 70.1,
6 | J. Name., 2012, 00, 1‐3
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1
ꢈ
ꢎ
71.1, 71.3, 74.1, 97.6, 101.8, 114.7, 115.1, 117.6, 118.1, 127.0, 10 ꢉ 2.10, ꢏꢍꢅꢏꢐꢅ . H NMR (CDCl3) δ: 1.09 (d, J= 6 Hz, 3H, Rha‐H6),
129.75, 129.95, 130.0, 132.7, 133.4, 145.8, 157.2, 160.6, 168.3, 1.93 (s, 3H, ‐COCH3), 1.96 (s, 6H, 2 x ‐COCH3), 2.01 (s, 3H, ‐COCH3),
170.0, 170.5, 170.6. HRMS (ESI+): m/z [M + H]+ calcd for C41H51O16: 2.07 (s, 3H, ‐COCH3), 2.80‐2.85 (m, 2H, ‐CH2CH2‐Ar), 3.64‐3.72 (m,
799.3177; found: 799.3170.
3H, Glu‐H5, Glu‐H2, ‐CH2aCH2‐Ar), 3.95‐4.04 (m, 1H, ‐CH2bCH2‐Ar),
4.16‐4.24 (m, 3H, Glu‐H6, Rha‐H5), 4.40‐4.47 (m, 5H, Glu‐H1, 2 x –
CH2‐CH=CH2), 4.88 (d, J= 1.5 Hz, 1H, Rha‐H1), 4.95‐5.02 (m, 3H, Glu‐
[2‐(4‐Allyloxyphenyl)]ethyl 2,4‐di‐O‐acetyl 3‐(2,3,4‐tri‐O‐acetyl α‐L‐ H4, Rha‐H4, Rha‐H2), 5.15‐5.38 (m, 6H, 2 x –CH2‐CH=CH2, Glu‐H3,
rhamnopyranosyl) 6‐Ο‐(E)‐4‐allyloxycoumaryl β‐D‐glucopyranoside Rha‐H3), 5.90‐6.05 (m, 2H, 2 x –CH2‐CH=CH2), 6.24 (d, J= 15.9 Hz, 1H,
19
ArCH=CHCOO‐), 6.76 (d, J= 8.7 Hz, 2H, ArH), 6.83 (d, J= 8.7 Hz, 2H,
ArH), 7.05 (d, J= 8.7 Hz, 2H, ArH), 7.39 (d, J= 8.7 Hz, 2H, ArH), 7.57 (d,
J= 15.9 Hz, 1H, ArCH=CHCOO‐). 13C NMR (CDCl3) δ: 17.2, 20.65,
To a mixture of acetylated 2‐orthoester 15 (100 mg, 0.12 mmol) and 20.68, 20.75, 20.82, 20.91, 35.2, 62.2, 66.6, 68.6, 68.80, 68.84, 69.1,
activated MS 4Å (200 mg) in round bottom flask under N2 70.3, 71.25, 71.28, 71.8, 74.7, 76.4, 97.7, 101.5, 114.8, 115.1, 117.6,
atmosphere was added anhydrous CH2Cl2 (10 mL). The mixture was 118.1, 127.1, 129.7, 129.8, 129.9, 132.7, 133.3, 145.3, 157.3, 160.5,
stirred for 30 min. and was then cooled down to ‐78 C before 166.8, 169.7, 169.9, 170.0, 170.1, 170.4. HRMS (ESI+): m/z [M + H]+
addition of TMSOTf (5 μl, 0.025 mmol). The reaction was stirred for calcd for C45H55O18: 883.3388; found: 883.3375.
at least 1 h whereupon TLC analysis showed complete conversion of
the starting material and a new spot with Rf = 0.65 (EtOAc: hexane =
1: 1). Et3N (20 μl) was then added into the reaction mixture which [2‐(4‐Allyloxyphenyl)]ethyl 3‐(α‐L‐rhamnopyranosyl) 6‐Ο‐(E)‐4‐
was stirred for 15 min and then allowed to warm to room allyloxycoumaryl β‐D‐glucopyranoside 21
temperature. The mixture was filtered through a pad of Celite®, the
filtrate was evaporated and the crude residue was purified by flash
column chromatography (EtOAc: hexane = 1: 3) to afford of 3‐ Deacetylation of glucopyranoside 19: glucopyranoside 19 (100 mg,
rhamnosylate
19
ꢎ
(91
mg,
86%
yield).
ꢁꢂꢃꢅꢄꢆ ꢇ 0.11 mmol) was dissolved in a mixture of CH2Cl2 (2 mL) and 40%
1
ꢈ
11 ꢉ 3.05, ꢏꢍꢅꢏꢐꢅ . H NMR (CDCl3) δ: 1.07 (d, J= 6.3 Hz, 3H, Rha‐ MeNH2 in MeOH (2 mL) maintained at 0 C and stirred overnight.
H6), 1.88 (s, 3H, ‐Ac), 1.96 (s, 3H, ‐Ac), 1.97 (s, 3H, ‐Ac), 2.03 (s, 3H, ‐ The reaction was then evaporated under reduced pressure and
Ac), 2.06 (s, 3H, ‐Ac), 2.73‐2.78 (m, 2H, ‐CH2CH2‐Ar), 3.51‐3.58 (m, purified by column chromatography (gradient EtOAc to EtOAc :
2H, Glu‐H5, ‐CH2aCH2‐Ar), 3.71 (t, J= 9.3 Hz, Glu‐H3), 3.80 (dd, J= 6.2, MeOH = 100 : 1) to afford deacetylated glucopyranoside 21 (50 mg,
9.6 Hz, 1H, Rha‐H5), 3.98‐4.01 (m, 1H, ‐CH2bCH2‐Ar), 4.11‐4.28 (m, 67% yield) as white amorphous solid.
2H, Glu‐H6), 4.36 (d, J= 7.8 Hz, 1H, Glu‐H1), 4.41 (dt, J= 1.5, 5.4 Hz,
2H, –CH2‐CH=CH2), 4.50 (dt, J= 1.5, 5.4 Hz, 2H, –CH2‐CH=CH2), 4.73
(d, J= 1.2 Hz, Rha‐H1), 4.94‐5.04 (m, 5H, Glu‐H2, Glu‐H4, Rha‐H2, Deacetylation of glucopyranoside 17: to
a
solution of
Rha‐H3, Rha‐H4), 5.18‐5.39 (m, 4H, 2 x –CH2‐CH=CH2), 5.92‐6.01 (m, glucopyranoside 17 (80 mg, 0.1 mmol) in anhydrous MeOH (2 mL)
2H, 2 x –CH2‐CH=CH2), 6.27 (d, J= 15.9 Hz, 1H, ArCH=CHCOO‐), 6.73 was added a solution of Mg(OMe)2 (6‐10 wt%) in MeOH (20 μl). The
(d, J= 8.7 Hz, 2H, ArH), 6.84 (d, J= 8.7 Hz, 2H, ArH), 7.02 (d, J= 8.7 Hz, reaction mixture was stirred at room temperature overnight. TLC
2H, ArH), 7.40 (d, J= 8.7 Hz, 2H, ArH), 7.59 (d, J= 15.9 Hz, 1H, analysis indicated complete consumption of the starting material
ArCH=CHCOO‐). From H‐H COSY, proton Glu‐H3 at δ3.71 showed a and formation of a new spot at Rf = 0.15 (pure EtOAc). The reaction
cross peak with acetylated Glu‐H2 and acetylated Glu‐H4 at δ4.94‐ mixture was quenched with saturated NaHCO3, and extracted with
5.04 thus confirming the formation of orthoester bond at O‐3 of the EtOAc (10 mL x 3). The combined organic phases were dried over
glucose unit. 13C NMR (CDCl3) δ: 17.3, 20.6, 20.75, 20.81, 20.9, 21.1, MgSO4, filtered and evaporated. The crude residue was purified by
35.1, 62.4, 67.5, 68.80, 68.84, 69.86, 69.92, 70.6, 70.7, 71.6, 72.1, column chromatography (gradient EtOAc to EtOAc : MeOH = 100 :
81.7, 99.6, 100.8, 114.6, 114.9, 115.1, 117.6, 118.1, 127.1, 129.9, 1) to give of deacetylated glucopyranoside 21 (49 mg, 73% yield) as
130.7, 132.7, 133.4, 145.2, 157.1, 160.5, 166.9, 169.4, 169.5, 169.6, white amorphous solid. After storage for few weeks, NMR analysis
170.1, 170.2. HRMS (ESI+): m/z [M + H]+ calcd for C45H55O18: of deacetylated glucopyranoside 21 indicated isomerization of the
883.3388; found: 883.3392.
alkenyl bond of p‐coumaroyl moiety resulting in E/Z = 10/1.[12]
1
[2‐(4‐Allyloxyphenyl)]ethyl 3,4‐di‐O‐acetyl 2‐(2,3,4‐tri‐O‐acetyl α‐L‐ ꢁꢂꢃꢅꢄꢆ ꢇ 35 ꢉ 1.90, ꢏꢍꢅꢏꢐꢅ . H NMR (CD3OD) δ: 1.17 (d, J= 6 Hz,
rhamnopyranosyl) 6‐Ο‐(E)‐4‐allyloxycoumaryl β‐D‐glucopyranoside 3H, Rha‐H6), 2.76 (t, J= 7.7 Hz, 2H, ‐CH2CH2‐Ar), 3.23‐3.34 (m, 2H),
ꢈ
ꢎ
20
3.42‐3.49 (m, 2H), 3.59‐3.64 (m, 2H), 3.81‐3.93 (m, 3H), 4.25 (d, J=
5.7 Hz, 1H, Glu‐1H), 4.30‐4.50 (m, 6H, Glu‐H6, 2 x –CH2‐CH=CH2),
5.10‐5.35 (m, 5H, Rha‐H1, 2 x –CH2‐CH=CH2), 5.87‐6.02 (m, 2H, 2 x –
Ac2O (0.5 ml) was added drop‐wise to
a
solution of 2‐ CH2‐CH=CH2), 6.30 (d, J= 15.9 Hz, 1H, ArCH=CHCOO), 6.62‐7.02 (m,
rhamonosylate 18 (80 mg, 0.1 mmol) in pyridine (0.5 ml, solvent). 6H, ArH), 7.38 (d, J= 8.7 Hz, 2H, ArH), 7.55 (d, J= 15.9 Hz, 1H,
The reaction was stirred at room temperature overnight then co‐ ArCH=CHCOO). 13C NMR (CDCl3) δ: 18.0, 36.6, 64.9, 69.9, 67.0, 70.2,
evaporation with toluene to remove excess pyridine and Ac2O. The 70.7, 72.4, 72.5, 74.1, 75.5, 75.8, 84.2, 102.9, 104.5, 115.8, 116.2,
crude residue was purified by flash column chromatography (EtOAc: 116.3, 117.5, 118.0, 128.5, 131.0, 131.2, 133.1, 134.6, 135.2, 146.5,
hexane = 1 : 3) to afford acetylated 2‐O‐rhamnosyl glucopyranoside 158.7, 162.2, 168.9. HRMS (ESI+): m/z [M + H]+ calcd for C35H45O13:
20 (84 mg, 96% yield) as white amorphous solid. ꢁꢂꢃꢅꢄꢆ ꢇ 673.2860; found: 673.2852.
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB00198C
ARTICLE
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2‐(4‐Hydroxyphenyl)ethyl 3‐(α‐L‐rhamnopyranosyl) 6‐Ο‐(E)‐4‐
hydroxycoumaryl β‐D‐glucopyranoside (osmanthuside‐B6) 1
A mixture of deacetylated glucopyranoside 21 (100 mg, 0.15 mmol),
Pd/C (10 wt%, 100 mg) and p‐TsOH (3 mg, 0.015 mmol) in MeOH
(2.7 mL) and H2O (0.3 mL) was heated at 80 C for 12 h. The
reaction mixture was filtered through a pad of Celite® and the
filtrate concentrated. Purification using column chromatography
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16.
17.
18.
19.
20.
21.
B6 1 (63 mg, 71% yield) as white solid. NMR data was in agreement
2
with the reported data. ꢁꢂꢃꢅꢄꢆ ꢇ 39 ꢉ 1.80, ꢊꢋꢌꢍ . 1H NMR
(CD3OD) δ: 1.17 (d, J= 6 Hz, 3H, Rha‐H6), 2.73 (t, J= 7.5 Hz, 2H, ‐
CH2CH2‐Ar), 3.23‐3.34 (m, 2H), 3.40‐3.50 (m, 2H), 3.59‐3.64 (m, 2H),
3.82‐3.93 (m, 3H), 4.23‐4.29 (m, 2H, Glu‐1H, H6a), 4.39‐4.43 (m, 1H,
H6b), 5.09 (d, J= 1.2 Hz, Rha‐H1), 6.25 (d, J= 15.9 Hz, 1H,
ArCH=CHCOO), 6.56 (d, J= 8.4 Hz, 2H), 6.70 (d, J= 8.4 Hz, 2H), 6.94 (d,
J= 8.4 Hz, 2H), 7.31, J= 8.4 Hz, 2H), 7.53 (d, J= 15.9 Hz, 1H,
ArCH=CHCOO). 13C NMR (CD3OD) δ: 18.0, 37.1, 64.8, 70.2, 70.6, 72.4,
72.5, 72.6, 74.1, 75.5, 75.8, 84.1, 102.9, 104.5, 115.1, 116.3, 117.0,
127.2, 130.7, 131.1, 131.4, 147.0, 156.9, 161.4, 169.2. HRMS (ESI+):
m/z [M + H]+ calcd for C29H37O13: 593.2234; found: 593.2236.
ꢈ
ꢎ
22.
23.
24.
25.
26.
Acknowledgements
We wish to thank Nanyang Technological University for financial
support.
Keywords: Phenylpropanoid glycosides • Osmanthuside-B6 •
Regioselective acylation • Disaccharide orthoesters isomerization
• Dimethyl tin dichloride
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8 | J. Name., 2012, 00, 1‐3
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