N-Pentenyl-Type Glycosides for Catalytic Glycosylation and Their Application in Single-Catalyst One-Pot Oligosaccharide Assemblies

Article abstract of DOI:10.1021/acs.orglett.9b03038

We have developed a new type of n-pentenyl-type glycosides that can be activated by catalytic amounts of promoter, Hg(NTf₂)₂ or PPh₃AuCl/AgNTf₂, at room temperature. The mild activation conditions and outstanding stability of common protection/deprotection manipulations enable the enynyl donors to have broad applications in constructing various glycosidic bonds. Furthermore, under the Hg(NTf₂)₂-catalyzed conditions, the sequential activation of different types of donors was achieved, based on which a gentiotetrasaccharide was synthesized via the newly developed single-catalyst one-pot strategy.

Full text of DOI:10.1021/acs.orglett.9b03038

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
n‑Pentenyl-Type Glycosides for Catalytic Glycosylation and Their
Application in Single-Catalyst One-Pot Oligosaccharide Assemblies
Yujia Zu,†,§ Chenglin Cai,†,§ Jingyuan Sheng,† Lili Cheng,† Yingle Feng,† Shengyong Zhang,†
Qi Zhang,*,‡ and Yonghai Chai*,†
†Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education, Xi’an, Shaanxi 710119, P. R. China
‡School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an, Shaanxi 710119, P. R. China
S
* Supporting Information
ABSTRACT: We have developed a new type of n-pentenyl-type glycosides that can be activated by catalytic amounts of
promoter, Hg(NTf2)2 or PPh3AuCl/AgNTf2, at room temperature. The mild activation conditions and outstanding stability of
common protection/deprotection manipulations enable the enynyl donors to have broad applications in constructing various
glycosidic bonds. Furthermore, under the Hg(NTf2)2-catalyzed conditions, the sequential activation of different types of donors
was achieved, based on which a gentiotetrasaccharide was synthesized via the newly developed single-catalyst one-pot strategy.
arbohydrates, one of three essential biological micro-
molecules, play significant roles in various life processes,
the Hung’s group6b and Demchenko’s group;6c Figure 1,
compd 4), have been reported. Despite remarkable advances,
the NPG(-type) methods still suffer from some limitations. For
example, NPG(-type)s usually need to be activated by
stoichiometric halonium promoters,4a which makes these
methods resource-inefficient. Additionally, unsatisfactory yield-
s7a and the intolerance of some acid-labile groups7b also have a
negative impact on the application of the current NPG(-type)
methods. Thus mild and catalytic glycosylation protocols based
on novel NPG mimics are still highly desirable.
Herein we report a mild and efficient metal-catalyzed
glycosylation approach by employing a new type of NPG-type
donor that contains both 4-n-pentenyl and 1,5-enynyl scaffolds
(Figure 1, compd 5). Different from the traditional activation
mode of NPG(-type)s,4a,6 which involves an electrophilic
addition of the olefin moiety toward stoichiometric halonium
promoters and a subsequent intermolecular cyclization
between the anomeric O and the in-site-generated halonium
ion, our donors are triggered by the activation of the remote
triple bond by catalytic amounts of soft metal ion (e.g., Hg(II)
or Au(I)) (Scheme 1). After a cascade process including an
intramolecular domino cyclization and a release of the
substituted tetrahydrofuran (THF) byproduct 10, the reactive
oxocarbenium G is formed and then reacts with an aglycone 6
to afford the desired glycosides 7.
C
such as cell−cell interactions, fertilization, and immunores-
ponse.1 Because the isolation of well-defined oligosaccharides
from natural sources is hardly accessible,2 chemical synthesis
becomes a reliable approach to obtain both natural and
unnatural oligosaccharides in homogeneous and scalable
forms. The stereoselective formation of glycosidic bonds is a
crucial part of the chemical synthesis of oligosaccharides, and
thus numerous glycosylation strategies utilizing different
glycosyl donors have been developed over recent decades.3−5
Among them, donors with a dually functional group in the
anomeric position, such as alkyl4a,b and thio groups,4c have
attracted considerable attention because they can not only
serve as glycosyl donors but also tolerate a variety of
protection/deprotection manipulations, which reduces the
overall steps of the oligosaccharide assemblies.
The 4-n-pentenyl glycosides (NPGs, Figure 1, compd 1),
introduced by Fraser-Reid,4a are one of the most important
Figure 1. Structures of previous NPG(-type) donors and our donors.
The novel NPG-type donors not only inherit the merits of
the traditional NPG donors such as the dual nature of the
anomeric group (as both a protecting group and a leaving
group) but also earn some new advantages, including the
dual donors due to their convenient preparation and versatile
applications. To date, more than 100 relevant papers and
several modified NPG-type versions,6 such as gem-dimethyl
analogs (developed by the Andrade’s group;6a Figure 1,
compds 2 and 3) and 2-allyloxyphenyl donors (developed by
Received: August 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03038
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Letter
a
Scheme 1. Mechanism for the Activation of Previous NPG(-
type) and Our NPG Mimics
Table 1. Optimization of Glycosylation Conditions
donor
(configuration of
CC)
time
(h)
yield
b
a
c
entry
cat. (mol %)
(%)
α/β
1
2
5a (Z)
5a (Z)
PPh3AuCl (10)
PPh3AuCl (10)
+ AgSbF6 (10)
6
6
NR
NR
3
4
5a (Z)
5a (Z)
PPh3AuCl (10)
+AgNTf2 (10)
PPh3AuCl (20)
+ AgNTf2 (20)
6
6
54
89
1:12
1:14
5
6
7
8
9
10
5a (Z)
5a (Z)
5a (Z)
5a (Z)
5a (Z)
5a-E (E)
5a-E (E)
Hg(OTf)2 (10)
Hg(NTf2)2 (10)
Hg(NTf2)2 (5)
Hg(NTf2)2 (1)
Hg(NTf2)2 (5)
Hg(NTf2)2 (5)
6
6
74
97
99
40
99
21
NR
1:13
1:9.2
1:16.2
0.5
24
0.5
0.5
6
d
1:16.3
1:16.7
catalytic amounts of promoters and the novel activation
pathway. Furthermore, these NPG-type donors and the related
activation conditions could be applied in the synthesis of
tetrasaccharides through an innovative single-catalyst one-pot
strategy for oligosaccharide assemblies.
Inspired by the metal-catalyzed cyclization reactions of 1,5-
enynyl compounds,8,9 we first chose an enynyl ether donor 5a
containing both 4-n-pentenyl and 1,5-enynyl moieties as NPG
mimics. The synthesis of 5a is shown in Scheme 2: α-D-
d
11
PPh3AuCl (20)
+ AgNTf2 (20)
a
b
Donor (1.5 equiv), acceptor (1 equiv), c = 0.05 M. Isolated yield.
c
d
1
Determined by H NMR. Donor (1.3 equiv), acceptor (1 equiv).
and afforded the expected disaccharide 7a in 54% yield with a
α/β ratio of 1:12 after 6 h (entry 3). The yield and the
anomeric selectivity could be further improved with the
increase in the catalyst amounts to 20 mol % (89%, α/β 1:14,
entry 4). The Hg(II) salts were also able to activate the new
NPG-type donors (entries 5 and 6). Among them, Hg(NTf2)2
was found to be the most efficient catalyst, giving the glycosyl
product 7a in almost quantitative yield (97%, entry 6). A
further effort was made to reduce the amounts of the Hg(II)
catalyst (entries 7−9). To our delight, 5 mol % of Hg(NTf2)2
also showed satisfactory catalytic activity without compromis-
ing yields and stereoselectivity in 30 min, irrespective of using
1.5 or 1.3 equiv of donor (entries 7 and 9). But unfortunately,
the lower catalyst loading (e.g., 1 mol %) led to a prolonged
reaction time and poorer reaction yields (entry 8). It is noted
that the geometric configuration of the double bond in the
anomeric group has a great effect on the glycosylation under
both the Au(I)- and Hg(II)-catalyzed conditions. Compared
with the (Z)-enynyl donor 5a, the (E) isomer 5a-E furnished
the desired disaccharide in much lower or even zero yield
(entries 10 and 11). This is probably because the (E) isomer is
more stable, and thus it is more difficult to cleave the
anomeric O-ether bond via the metal-catalyzed cascade
cyclization, which requires a destruction of the large
conjugated system in the enynyl moiety. Therefore, the
glycosidic bonds proved to be constructed with (Z)-enynyl
ether as the new NPG-type donor under the conditions of 5
mol % Hg(NTf2)2 in CH2Cl2 at rt for 30 min (entry 9, the
optimal condition) or 20 mol % PPh3AuCl/20 mol % AgNTf2
as the catalyst in CH2Cl2 at rt for 6 h (entry 4).
Scheme 2. Synthesis of Enynyl Ether Donor 5a
Acetobromoglucose 1410 first reacted with enynyl alcohol 13,
which was obtained from the Lindlar reduction of the triple
bond in compound 1111 and the subsequent Sonogashira
coupling with hex-1-yne, giving the O-Ac-protected orthoester
15. After the removal of Ac groups, followed by the protection
by Bn groups, the tri-O-benzyl orthoester 16 was attained. By
the catalysis of TMSOTf, 16 underwent the orthoester
rearrangement to deliver the desired enynyl ether donor 5a.
(For the synthesis of other donors, including 5a-E, see the SI.)
Next, the glycosylation conditions were explored using 5a as
the donor and 6a as the acceptor in CH2Cl2 at room
temperature (rt) (Table 1). A variety of metal catalysts were
examined, and it was found that no glycosyl product was
formed with 10 mol % of the catalytic candidates, such as
In(OTf)3, RuCl3, (PPh3)3RhCl, Pd(OAc)2, Cu(OTf)2, Fe-
(OTf)3, AgNTf2, AuCl, and AuCl3. (See Table S1.) PPh3AuCl
could not promote this conversion with or without the
cocatalyst AgSbF6 (entries 1 and 2); however, when the
cocatalyst was changed to AgNTf2, the glycosylation occurred
Author: With the optimal glycosylation condition in hand,
we set out to investigate the substrate scope of this new
glycosylation method (Table 2). Gratifyingly, both armed and
disarmed NPG-type donors, such as Glu, Gal, L-Rha, and Man,
could couple to acceptor 6 to deliver the corresponding
glycosides 7 in good to excellent yield in 30 min (7a−f). A
B
DOI: 10.1021/acs.orglett.9b03038
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a b c
, ,
the catalysis of PPh3AuCl/AgNTf2, the targeted glycosyl
products were also obtained in good to excellent yield no
matter whether using glucosyl, galactosyl, or rhamnosyl donors
(7ae−ce).
Table 2. Substrate Scope
To ensure the dual functionality of the new NPG mimics,
their stability was evaluated through the synthesis of various
sugar building blocks bearing different protecting groups. (See
Scheme S1.) It was proved that the anomeric enynyl ether
tolerated a great deal of protection/deprotection manipu-
lations involved in acidic (e.g., TMSOTf, 80% acetic acid
solution) or basic (e.g., NaH, MeONa) conditions, which
indicates that apart from a leaving group, the enynyl group
could also act as a suitable protecting group for the anomeric
position of sugar rings. This stability enables the new NPG-
type glycosides to be applied to the rapid synthesis of glycan
and glycoconjugates.
The new enynyl glycosylation approach was also applied to
the synthesis of dioscin, a cytotoxic steroidal saponin.12
Starting from per-O-benzoylated enynyl glucoside 5j and
diosgenin, dioscin was obtained in 68% overall yield after a
five-step conversion. (See Scheme S2.)
On the basis of some control experiments (see Scheme S3)
and literature reports,8,9 a plausible mechanism was proposed
(Scheme 1). The coordination of the Hg(II) or Au(I) ion to
the triple bond in the enynyl ether triggers the nucleophilic
attack of the olefin moiety to the alkyne moiety via a 5-endo-dig
pathway,8,9 followed by the intramolecular addition of the
anomeric O to the in- situ-generated cation to produce
intermediate E. The subsequent cleavage of the anomeric C−
O bond delivers the putative oxocarbenium ion G or related
intermediates13 with the release of mercury or gold complex F.
The attack of an nucleophilic acceptor 6 to the putative
oxocarbenium ion G or related intermediates leads to the
formation of the desired glycoside 7. Protodemetalation of
complex F affords the THF derivative 10 with the regeneration
of the active Hg(II) or Au(I) species.
The assembly of oligosaccharides is always a formidable task
because of the multiple protection/deprotection manipulations
and the time-consuming intermediate purifications. In the past
decades, various synthetic strategies have been developed,
among which one-pot glycosylation methods,14−17 including
chemical selective,15 orthogonal,16 and preactivation-based17
protocols, have made great contributions to highly improving
the efficiency of the oligosaccharide assemblies.
a
b
Donor (1.3 equiv), acceptor (1 equiv), c = 0.05 M. Isolated yield.
c
d
e
1
Determined by H NMR. Donor (3 equiv). Donor (1.3 equiv),
Considering that the Hg(II) salts are not only good
alkynophilic compounds as a π acid8a,9 but also good oxo/
azaphilic compounds as a Lewis acid,18 we then launched an
exploration of the possibility of the one-pot synthesis of
oligosaccharides by using different reactive acid-activatable
glycoside moieties with catalytic amounts of Hg(NTf2)2 as the
single promoter. To this end, the reactive sequences of several
disarmed glycosyl donors bearing different acid-activatable
leaving groups on the anomeric position, including the
trichloroacetimidates, Yu’s O-alkynylbenzoates, our enynyl
ethers, and the pentenyl ethers, were evaluated, and the results
are depicted in Scheme 3. The glycosylation of per-O-pivaloyl
glycosyl trichloroacetimidate 17 and per-O-benzoyl glycosyl
alkynylbenzoate 18 with rhamnosyl acceptor 6a was first
conducted under the conditions of 5 mol % of Hg(NTf2)2 in
dichloromethane (DCM) for 5 min, furnishing the pivaloyl
rhamnosyl glycoside 7t in 94% yield with quantitative
alkynylbenzoate 18 recovered. The big reactive difference
was also represented between glycosyl O-alkynylbenzoate 18
acceptor (1 equiv), Ph3PAuCl (20 mol %), AgNTf2 (20 mol %),
CH2Cl2 (c = 0.05 M), rt, 6 h.
wide range of glycosyl acceptors also performed well in the
glycosylation reaction, regardless of being sugar or nonsugar
nucleophiles or hindered or unhindered nucleophiles (7g−o).
This catalytic system is compatible with a number of
commonly used protecting groups in carbohydrate chemistry,
including acyl, benzyl, allyl, and acid-labile ketal, acetal, and
silyl (TBS and TBDPS) groups (7p,q). In particular, the
glycosylation was also achieved with acceptors bearing an n-
pentenyl or thiophenyl anomeric group, which demonstrates
the orthogonality between our new NPG-type donors and the
traditional NPG/thio-glycosides under the optimal conditions
(7r,s). It should be mentioned that the Hg(II) catalyst could
be removed by commercially available mercaptoalkyl-function-
alized silica MK-I (purchased from Shanghai Macklin
Biochemical; for details, see Table S2). In addition, under
C
DOI: 10.1021/acs.orglett.9b03038
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under the same Hg(NTf2)2 catalyst. After that, pentenyl
acceptor 6f was injected in the vessel to react with the
trisaccharide intermediate. After 30 min, the protected
tetrasaccharide 21 was formed in 73% overall yield by the
catalysis of Hg(NTf2)2 in the reaction system. That is to say,
glycosidic bonds between four different glycosyl donors could
be sequentially constructed with the same Hg(II) catalyst
within 40 min in a high total yield. To the best of our
knowledge, this is the first time a tetrasaccharide has been
assembled using a single catalyst in one pot. After the global
deprotection of the Piv and Bz groups, the target
gentiotetrasaccharide 22 was finally achieved in 97% yield.
We have developed a versatile and highly efficient catalytic
glycosylation approach by using novel NPG mimics containing
both 4-n-pentenyl and 1,5-enynyl moieties as glycosyl donors.
Under the mild Hg(II)- or Au(I)-catalyzed conditions, both
armed and disarmed donors could couple to diverse acceptors,
affording the corresponding glycosides in good to excellent
yield (up to 99%). The anomeric enynyl group proved to be
stable during various protection/deprotection manipulations,
allowing this approach to have broad applications in the
expeditious synthesis of glycans and glycoconjugates. In the
Hg(II) catalytic system, the reactive sequence of several acid-
activatable glycosides was also disclosed, based on which a
tetrasaccharide was rapidly assembled in a satisfactory yield via
a single-catalyst one-pot synthetic strategy for oligosaccharides.
Scheme 3. Exploration of Reactive Sequence of Various
Donors
and enynyl ether 5i. With the catalytic amount of Hg(NTf2)2,
almost all of alkynylbenzoate 18 was transformed into
disaccharide 7u, whereas the enynyl ether 5i was recovered
in 91% yield. For the glycosyl enynyl ether and pentenyl ether
pair, the formation of disaccharide 7s in Table 2 has already
exhibited that the enynyl ether 5i is more reactive than the
pentenyl ether 6f. Therefore, it could be concluded that the
above four types of donors possess different reactivities under
the activation of the Hg(NTf2)2 catalyst, and the reactive
sequence is glycosyl trichloroacetimidates > O-alkynylben-
zoates > enynyl ethers > pentenyl ethers.
On the basis of this reactive sequence, a single-catalyst one-
pot assembly of gentiotetrasaccharide 22, which was found in
lichens and can be used as a bifidus factor to promote animal
growth,19 was carried out (Scheme 4). Initially, per-O-pivaloyl
glycosyl trichloroacetimidate 17 and bifunctional glycosyl
alkynylbenzoate acceptor 19 were treated with 5 mol % of
Hg(NTf2)2 for 5 min. Then, bifunctional enynyl glycosyl
acceptor 20 was added to couple to the newly formed
disaccharide intermediate, affording the trisaccharide in 5 min
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03038.
1
Experimental details and H and 13C NMR spectra for
all new compounds(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: qiqizhang@snnu.edu.cn (Q.Z.).
*E-mail: ychai@snnu.edu.cn (Y.C.).
ORCID
Qi Zhang: 0000-0002-9306-055X
Yonghai Chai: 0000-0003-3157-179X
Author Contributions
§Y.Z. and C.C. contributed equally.
Notes
Scheme 4. Single-Catalyst One-Pot Synthesis of
Tetrasaccharide
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (nos. 21072122, 21472119), the Science
and Technology Program of Shaanxi Province, China
(2018ZDXM-GY-152), and the Fundamental Research
Funds for the Central Universities (GK201701002,
GK201603036). All of the financial support is gratefully
acknowledged.
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DOI: 10.1021/acs.orglett.9b03038
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