Short synthesis of phenylpropanoid glycosides calceolarioside-B and eutigoside-A

Article abstract of DOI:10.1016/j.tetlet.2016.11.116

A convenient 4-step synthesis of calceolarioside-B 1 and eutigoside-A 2 in high overall yield is described. The key step involved the regioselective, Me₂SnCl₂-catalyzed O-6 acylation of unprotected 2-phenylethyl-β-D-glucosides 5a–b with cinnamoyl chlorides 6a–b in excellent yields. Acylation at O-6 is selective with the acid chlorides used. This work serves as a model for the convenient synthesis of phenylpropanoid glycosides acylated at O-6.

Full text of DOI:10.1016/j.tetlet.2016.11.116

Accepted Manuscript
Short synthesis of phenylpropanoid glycosides calceolarioside-B and eutigo-
side-A
Duc Thinh Khong, Zaher M.A. Judeh
PII:
S0040-4039(16)31607-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.116
TETL 48402
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
3 November 2016
22 November 2016
28 November 2016
Please cite this article as: Khong, D.T., Judeh, Z.M.A., Short synthesis of phenylpropanoid glycosides
calceolarioside-B and eutigoside-A, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.11.116
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Short synthesis of phenylpropanoid
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glycosides calceolarioside-B and eutigoside-A
Duc Thinh Khong, Zaher M. A. Judeh

1
Tetrahedron Letters
Short synthesis of phenylpropanoid glycosides calceolarioside-B and eutigoside-A
Duc Thinh Khong, Zaher M. A. Judeh 
*
School of Chemical and Biomedical Engineering, Nanyang Technological University, 62 Nanyang Drive, N1.2–B1-14, Singapore 637459
ARTICLE INFO
ABSTRACT
A convenient 4-step synthesis of calceolarioside-B 1 and eutigoside-A 2 in high overall yield is
described. The key step involved the regioselective, Me2SnCl2-catalyzed O-6 acylation of
unprotected 2-phenylethyl-β-D-glucosides 5a-b with cinnamoyl chlorides 6a-b in excellent
yields. Acylation at O-6 is selective with the acid chlorides used. This work serves as a
model for the convenient synthesis of phenylpropanoid glycosides acylated at O-6.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Phenylpropanoid glycosides
Calceolarioside-B
Eutigoside-A
Regioselective acylation
Dimethyltin dichloride
1. Introduction
lines including prostatic cancer cells,8 human bladder carcinoma
T-24 cells,14 human gastric adenocarcinoma,15 human uterus
carcinoma,15 and murine melanoma.15 Despite their structural
simplicity, their syntheses have been reported using multistep
Phenylpropanoid glycosides (PhGs) are secondary
metabolites that are widely distributed in plants and show
antioxidation, antiproliferation, antibacterial, antiviral, anti-
inflammatory and hepatoprotection activities.1,2 Simple PhGs
contain a 2-phenylethyl-β-D-glucoside core unit acylated with a
cinnamoyl moiety, mainly at O-4 or O-6 (Fig. 1) while more
complex PhGs contain an additional one or two saccharide units
bonded to the glucose core through glycosidic bonds.
procedures
with
extensive
and
cumbersome
protection/deprotection steps.3, 8
The total synthesis of PhGs has attracted significant interest
from medicinal and synthetic chemists to uncover their potential.
However, their synthesis has mainly relied on tedious, low-
yielding and multistep protection-deprotection strategies in order
to assemble the cinnamoyl moiety at the correct position on the
glucose core.3-11 These strategies are further complicated by the
incompatibilities between the cinnamoyl and the protecting
groups under the conditions for protection/deprotection. For
example, when benzyl ether protecting groups were removed by
hydrogenolysis, reduction of the cinnamoyl moieties olenfinic
bonds occurred.3,5,11 Likewise, removal of the acetyl and
chloroacetyl protecting groups resulted in hydrolysis and/or
migration of the cinnamoyl moieties.9,10 Recently, Mong and co-
workers 8 successfully reported an orthogonal multistep synthesis
of calceolarioside-B 1 and other PhGs. The synthesis relied on a
protection/deprotection methodology using naphthylidene acetal,
naphthylmethyl and allyl ether protecting groups that were
selectively removed.
Figure 1. Structures of calceolarioside-B 1 and eutigoside-A 2
Herein, we report a convenient, high-yielding synthesis of
calceolarioside-B
1
and
eutigoside-A
2
without
protection/deprotection steps. The synthetic strategy relies on a
regioselective Me2SnCl2-catalyzed O-6 acylation of an
unprotected glucose core. The strategy is applicable to the
synthesis of phenylpropanoid glycosides acylated at O-6.
2. Results and Discussion
Our proposed synthetic route for calceolarioside-B 1 and
eutigoside-A 2 entails two main steps as outlined in Scheme 1.
The first step involves 1,2-tran-β-glycosylation of peracetylated
D-glucose 3 with 2-phenylethanols 4 through a neighboring group
participation mechanism to give 2-phenylethyl-β-D-glucoside 5.
The second key step involves the regioselective O-6 acylation of
Calceolarioside-B 112 and eutigoside-A 213,14 (Fig. 1) possess
potential antiproliferation activities against various tumor cell
———
 Corresponding author. Tel.: +65-6790-6738; fax: +65-6794-7553; e-mail: zaher@ntu.edu.sg

2
Tetrahedron
the unprotected 2-phenylethyl-β-D-glucoside 5 with cinnamoyl
glucose 3 provided the desired glucosides in higher yields
chlorides 6.
compared to stoichiometric amounts, this complicated the
purification process. Because we were unable to separate pure
glucosides 11a-b, their crude glycosylation reaction mixtures
were subjected to deacetylation using NaOMe/MeOH. After
complete deacetylation and purification using column
chromatography, pure 2-phenylethyl-β-D-glucosides 5a-b were
obtained in 82% and 73% yield, respectively.
Scheme 1. Proposed synthetic route for calceolarioside-B 1 and
eutigoside-A 2
2-Phenylethanols 4 were prepared in two steps (Scheme 2).
Protection of the hydroxyl group of 4-hydroxyphenyl acetate
ester 7a with allyl bromide gave the O-allyl ester 8a in 87%
yield.16 Protection of the hydroxyl groups of 3,4-
dihydroxyphenyl acetate ester 7b with tert-butyldimethylsilyl
chloride (TBSCl) gave the O,O-diTBS ester 8b in 86% yield.4
Ester 7b was protected with TBSCl rather than allyl bromide
because we found that treatment of O,O-diallyl esters with Pd/C
always led to incomplete deprotection. Reduction of esters 8a-b
to the corresponding 2-phenylethanols 4a-b was achieved using
LiBH417 in 91% and 83% yield, respectively.4, 9
Scheme 3. Synthesis of calceolarioside-B 1 and eutigoside-A 2
Next, we examined the direct regioselective O-6 acylation of
2-phenylethyl-β-D-glucosides 5a-b with cinnamoyl chlorides 6a-
b using various Lewis acids including Me2SnCl2,22 Sn(OTf)2,23
24
Cu(OTf)2,23 Yb(OTf)3 and Sc(OTf)3.25,26 We also attempted the
acylation reaction under basic conditions using pyridine.9,27,28 The
reactions gave 67%-94% yields of mixtures containing multiple
acylation products (mainly O-4 and O-6 mixtures). However,
22
after optimization, Me2SnCl2 gave the desired O-6 acylated
glucosides 12a-b in 86% and 72% yield, respectively (Scheme
3). Direct acylation without catalysts is dependent on the type of
cinnamoyl chloride and reaction conditions.9, 27, 28
Scheme 2. Synthesis of 2-phenylethanols 4a-b and cinnamoyl
chlorides 6a-b
Finally, deprotection of the allyl groups of glucoside 12a using
Pd/C gave eutigoside-A 2 in 81% yield while deprotection of the
TBS groups of glucoside 12b using tetra-n-butylammonium
fluoride (TBAF) gave calceolarioside-B 1 in 67% yield. The
structures of both calceolarioside-B 1 and eutigoside-A 2 were
Cinnamoyl chlorides 6 were also prepared in two steps
(Scheme 2). The hydroxyl group of coumaric acid 9a was
protected using allyl bromide to give O-allyl coumaric acid 10a
in 91% yield.18 The hydroxyl groups of caffeic acid 9b were
protected using TBSCl to give O,O-diTBS cafeic acid 10b in
88% yield (Scheme 2).19 Conversion of acids 10a-b to their acid
chlorides 6a-b was readily achieved in quantitative yield by
heating at reflux with SOCl2 in CH2Cl2.20,21 These acid chlorides
were recrystallized from anhydrous toluene prior to acylation
with 2-phenylethyl-β-D-glucoside 5a-b.
1
confirmed by H NMR and 13C NMR and matched with the
reported data.8, 14
3. Conclusion
We have developed
a
short 4-step synthesis of
calceolarioside-B 1 and eutigoside-A 2 that avoids troublesome
protection/deprotection approaches and their incompatibilities
with the cinnamoyl moieties. Both calceolarioside-B 1 and
eutigoside-A 2 were obtained, respectively, in excellent 35% and
57% overall yields. The key step in this synthesis involved the
regioselective Me2SnCl2-catalyzed O-6 acylation of unprotected
2-phenylethyl-β-D-glucosides 5a-b with cinnamoyl chlorides 6a-
b. In our approach, acylation at O-6 is selective with the acid
chlorides used. Because of convenience and high yields, this
work is envisioned to serve as a model for the direct synthesis of
PhGs acylated at O-6.
Having synthesized the required 2-phenylethanols 4a-b and
cinnamoyl chlorides 6a-b, we then proceeded with the synthesis
of calceolarioside-B 1 and eutigoside-A 2 according to our
proposed route (Scheme 1). To obtain glucoside 5, 1,2-trans-β-
glycosylation is traditionally performed between 2-
phenylethanols and protected D-glucose containing bromide,
chloride and trichloroacetimidate leaving groups at C1.11 In this
work, direct glycosylation between 2-phenylethanols 4a-b and
excess peracetate D-glucose
3 using BF3·OEt2 gave the
corresponding glucosides 11a-b.3 Although excess peracetate D-

3
27.
Panda, P.; Appalashetti, M.; Natarajan, M.; Chan-Park,
Acknowledgment
M. B.; Venkatraman, S. S.; Judeh, Z. M. A. Eur. J. Med.
Chem. 2012, 53, 1.
28. Panda, P.; Appalashetti, M.; Natarajan, M.; Mary, C.-P.;
Venkatraman, S. S.; Judeh, Z. M. A. Eur. J. Med. Chem.
2012, 58, 418.
We acknowledge financial support from Nanyang Technological
University.
Supplementary data
1
Supplementary data (experimental procedures, H NMR and 13C
NMR spectra of synthesized compounds) associated with this
article can be found, in the online version, at…
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4
Tetrahedron
Highlights:
 Short synthesis of calceolarioside-B and eutigoside-A
 General route applicable to the synthesis of PhGs acylated at O-6
 Acylation at O-6 is selective
 No protection/deprotection steps