Practical synthesis of latent disarmed S-2-(2-propylthio)benzyl glycosides for interrupted Pummerer reaction mediated glycosylation

Article abstract of DOI:10.1016/j.tetlet.2017.05.014

Practical synthetic methods to latent disarmed S-2-(2-propylthio)benzyl (SPTB) glycosides for interrupted Pummerer reaction mediated glycosylation have been discovered. Among them, both coupling reaction of PTB-Cl with glycosyl thiols and BF₃·OEt₂ promoted reaction of peracylated glycosides with PTB-SH produced peracylated SPTB glycosides in large scales and with high efficiency.

Full text of DOI:10.1016/j.tetlet.2017.05.014

Accepted Manuscript
Practical Synthesis of Latent Disarmed S-2-(2-Propylthio)benzyl Glycosides for
Interrupted Pummerer Reaction Mediated Glycosylation
Yang Xu, Qian Zhang, Ying Xiao, Pinru Wu, Wei Chen, Zejin Song, Xiong
Xiao, Lingkui Meng, Jing Zeng, Qian Wan
PII:
S0040-4039(17)30585-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.014
TETL 48907
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 March 2017
4 May 2017
5 May 2017
Please cite this article as: Xu, Y., Zhang, Q., Xiao, Y., Wu, P., Chen, W., Song, Z., Xiao, X., Meng, L., Zeng, J.,
Wan, Q., Practical Synthesis of Latent Disarmed S-2-(2-Propylthio)benzyl Glycosides for Interrupted Pummerer
Reaction Mediated Glycosylation, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.05.014
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Practical Synthesis of Latent Disarmed S-2-
(2-Propylthio)benzyl Glycosides for
Interrupted Pummerer Reaction Mediated
Glycosylation
Yang Xu, Qian Zhang, Ying Xiao, Pinru Wu, Wei Chen, Zejin Song, Xiong Xiao, Lingkui Meng, Jing Zeng and
Qian Wan

1
Tetrahedron Letters
jour nal h om e pag e: w w w .elsevier .c om
Practical Synthesis of Latent Disarmed S-2-(2-Propylthio)benzyl Glycosides for
Interrupted Pummerer Reaction Mediated Glycosylation
Yang Xua,1, Qian Zhanga,1, Ying Xiaoa, Pinru Wua, Wei Chena, Zejin Songa, Xiong Xiaoa, Lingkui Menga,
Jing Zenga and Qian Wana, b
∗
a Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Huazhong University of Science and Technology, 13
Hangkong Road, Wuhan, Hubei, 430030, China
b Institute of Brain Research, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Practical synthetic methods to latent disarmed S-2-(2-propylthio)benzyl (SPTB) glycosides for
interrupted Pummerer reaction mediated glycosylation have been discovered. Among them, both
coupling reaction of PTB-Cl with glycosyl thiols and BF3•OEt2 promoted reaction of peracylated
glycosides with PTB-SH produced peracylated SPTB glycosides in large scales and with high
efficiency.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
interrupted Pummerer reaction
thioglycoside
disarmed glycoside
glycosyl donor
∗ Corresponding author.
e-mail: wanqian@hust.edu.cn
1

2
Although the vital functions of oligosaccharides and
glycoconjugates in biological process have promoted the
Although this procedure provided various SPTB glycosides in
good yields, the instability of PTB-I limited its application
especially in large scale synthesis. We then considered to replace
PTB-I with more stable PTB-Cl 7 which was efficiently
synthesized from 2-(2-propylthio)benzyl alcohol. It is much
stable than PTB-I and could be kept for several months in fridge.
The further coupling of compound 7 with glycosyl thiols 2
furnished SPTB glycosides 4a-e in roughly equal efficiency to
the reaction with PTB-I 3 (Scheme 2). The synthesis in gram-
scale still offered 4a in 84% yield. During the further reaction
explorations, we found that glycosylation with peracetylated
glycosyl donors sometimes led to intermolecular acetyl transfer
byproducts.13,15 These side reactions could be suppressed by
changing the acetyl protecting group to benzoyl group.15c-e The
perbenzoylated SPTB glycosides (4f, 4g) could be obtained in
good yields under the same reaction conditions.
extraordinary
achievements
in
oligosaccharides
and
glycoconjugates synthesis over the decades, the remaining
challenges still encouraged the carbohydrate chemists to discover
new glycosylation strategies.1 Among those efforts, the
development of glycosyl donors with novel anomeric leaving
groups occupies an important niche. In addition to the traditional
and widely used glycosyl donors,2 several new types of glycosyl
donors such as propargyl glycosides,3 3,3-difluoro-3H-indole-2-
yl (OFox) glycosides,4 ortho-alkynylbenzoyl/benzyl glycosides,5
S-but-3-ynyl thioglycosides,6 4-p-methoxyphenyl-3-butenyl
thioglycosides7 and mannosyl 2,6-lactone8 etc. have been
successfully discovered and applied into the construction of
glycosidic bonds in past ten years. Very recently, we have
developed O-2-(2-propylsulfinyl)benzyl (OPSB) glycosides
which were simply obtained from oxidation of corresponding
latent O-2-(2-propylthio)benzyl (OPTB) glycosides as active
glycosyl donors (Scheme 1a).9 This new type of OPSB glycosyl
donors could be efficiently activated with Tf2O via an interrupted
Pummerer reaction.10 In addition, the intrinsic properties of
OPTB and OPSB glycosides allows the successfully application
of latent-active strategy11 in oligosaccharide synthesis. Due to
these O-benzyl glycosyl donors limited to “armed” and “super
armed” glycosides,12 we further discovered their S-analogues, S-
2-(2-propylthio)benzyl (SPTB) glycosides and S-2-(2-
propylsulfinyl)benzyl (SPSB) glycosides, as a new pair of latent-
active donors (Scheme 1b).13 This O to S replacement enabled the
remote activation of corresponding disarmed glycosyl donors via
interrupted Pummerer reaction. To further streamline the
applicability of active SPSB glycosyl donors, herein, we reported
practical synthetic methods to the latent disarmed S-2-(2-
propylthio)benzyl (SPTB) glycosides.
Scheme 3. Synthesis of PTB-SH 9.
Although high efficiency was achieved in this protocol, one
drawback is that some glycosyl thioacetates 1, such as 2-
aminoglucosyl
thioacetate,
mannosyl
thioacetate
and
Scheme 1. Interrupted Pummerer reaction mediated glycosylation.
rhamonnosyl thioacetate could not be obtained in good yields.14
Thus, we considered to further improve the efficiency of the
preparations by direct coupling of peracetylated glycosides 10
with 2-(2-propylthio)benzyl thiol (PTB-SH, 9). First, PTB-SH
was synthesized from PTB-Cl by thioacetylation and subsequent
removal of acetate group by LiAlH4 reduction. This two-steps
protocol furnished PTB-SH in excellent yields even in multi-
grams’ synthesis (Scheme 3). It should be noted that deprotection
of the acetate group under basic conditions led to low yields due
to the formation of disulfide.
Table 1. Optimization of the coupling reaction conditions of 10b
with 9.
Scheme 2. Synthesis of disarmed SPTB glycosides by coupling of
PTB-Cl with glycosyl thiols. a Yields of two steps reaction including
selective deacetylation of 1 to form 2 and subsequent coupling with
7，unless specified, the reactions were carried out in 0.1-0.5 mmol
Entry
Activator
Solvent
Time (h)
Yields (%)a
b
c
scale. Yield of reaction with PTB-I in parentheses. Yield with
PTB-Cl in 1.5 grams scale synthesis. DTT = 1,4- dithiothreitol,
DMA = dimethylacetamide.
1
TMSOTf
BF3•OEt2
BF3•OEt2
BF3•OEt2
BF3•OEt2
BF3•OEt2
DCM
DCM
MeCN
toluene
THF
4
63
92
68
84
-
2
24
9
Original synthetic method to latent disarmed S-2-(2-
propylthio)benzyl (SPTB) glycosides (4, Scheme 1c) involved
two-step sequence: selective deacetylation of glycosyl
thioacetates 1 to produce glycosyl thiols 214 and subsequent
coupling of 2 with 2-(2-propylthio)benzyl iodide (PTB-I, 3).13
3
4
9
5
9
6b
DCM
24
94

3
dichloroethane (DCE) and increasing the reaction temperature16
7b,c
BF3•OEt2
DCM
0.5
94
led to a full transformation of starting materials, a mixture of
anomeric isomers containing unseprable unknown byproducts
were obtained. To solve this problem, the anomeric benzoyl
groups of 11a and 11b were transformed to acetyl groups to
produce 12a and 12b in excellent yields. The coupling reactions
of 9 with 12a/b promoted by BF3•OEt2 under room temperature
proceeded smoothly which offered perbenzoylated SPTB
glycosides 4m and 4n in perfect yields.
a Isolated yield
b 3.0 Equiv of BF3⋅OEt2 was used
c Concentration increased to 0.5 M
The coupling reaction of compound 10b with PTB-SH 9 was
then explored. TMSOTf promoted this reaction in DCM offered
4b in moderated yield (Table 1, entry 1). Changing the activator
from TMSOTf to BF3•OEt2 resulted in 92% yield, albeit
requirement of much longer reaction time (entry 2). Screening of
the solvents to MeCN, toluene or THF furnished diminished
results (entries 3-5). Further increasing the amount of BF3•OEt2
didn’t apparently accelerate the reaction speed (entry 6).
Interestingly, carrying out the reaction in higher concentration
(0.5M) largely shortened the reaction time to 0.5 h without
affecting the reaction yield (entry 7).
In conclusion, we have reported practical synthetic methods
to latent disarmed SPTB glycosides. According to these methods,
the peracylated SPTB glycosides could be obtained efficiently
either by direct coupling of 7 (PTB-Cl) with glycosyl thiols or by
BF3•OEt2 promoted reaction of peracylated glycosides with 9
(PTB-SH). Both methods could offer the SPTB glycosides in
large scales and in excellent yields. Comparatively speaking, the
former method had broader substrates scopes which were only
limited by the availability of thioacetates, while the later method
was more direct albeit it was not suitable for pentopyranose and
lactose. We believe that these methods would benefit those
chemists who want to employ the interrupted Pummerer reaction
mediated glycosylation in complex oligosaccharides and
glycoconjugates synthesis. These methods are also helpful for
other disarmed thioglycosides synthesis.
Acknowledgments
This research is partially supported by National Natural
Science Foundation of China (21672077, 21402055, 21472054),
the State Key Laboratory of Bio-organic and Natural Products
Chemistry (SKLBNPC13425), Natural Science Funds of Hubei
Province for Distinguished Young Scholars (2015CFA035),
“Thousand Talents Program” Young Investigator Award, Wuhan
Creative Talent Development Fund and Huazhong University of
Science and Technology (2014ZZGH015) for support.
Scheme 4. Synthesis of SPTB glycosides by coupling of PTB-SH
with 1-O-acetyl glycosides. a Ac2O (20.0 equiv), AcOH (10.0 equiv),
Supplementary Material
b
H2SO4 (1.05 equiv), DCM, rt; Unless specified, reactions were
Supplementary data associated with this article can be found,
at
carried out in 50 mg scale. c Reactions were carried out in gram scale.
d Reaction concentration was 0.1 M.
in
http://dx.doi.org/10.1016/j.tetlet.2017.01.006.
the
online
version,
This optimized reaction conditions were applied to various
peracylated glycosides, and the latent SPTB glycosyl donors
were obtained in good to excellent yields (Scheme 4). The
syntheses of 4a and 4b in gram-scale were achieved in excellent
yield. The 6-deoxysugars 4h and 4i were prepared in high
efficiency. Aminosugar 4j was successfully produced in excellent
yield in gram scales. Notably, the solvent concentration should be
diluted to 0.1 M when producing pentose 4k and 4l, diminished
yields were observed in high concentration due to side reactions
in these two cases. It is worth noting that anomeric mixtures were
obtained for 6-deoxysugars (4h, 4i) and pentose (4k, 4l).
However, we didn’t try to further optimize the reaction
conditions to improve the anomeric selectivity, because it was
found that the ratio of the anomeric mixture didn’t affect the
efficiency and selectivity in later interrupted Pummerer reaction
mediated glycosylations.13 Unfortunately, the reactions with
peracetylated xylopyranose and lactose produced low yields.
The direct coupling of perbenzoylated glycosides 11 with
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Highlights:
ꢀ
ꢀ
ꢀ
Two practical synthetic methods to disarmed SPTB
glycosides are reported.
Both methods can make SPTB glycosides in gram
scale.
Affords an easy access to various disarmed SPTB
glycosides in high yields.