Glycosylation with 3,5-Dimethyl-4-(2′-phenylethynylphenyl)phenyl (EPP) Glycosides via a Dearomative Activation Mechanism

Article abstract of DOI:10.1021/jacs.9b00210

A highly effective and versatile glycosylation method is developed, which uses 3,5-dimethyl-4-(2′-phenylethynylphenyl)phenyl (EPP) glycosides as donors and NIS/TMSOTf as promoter and proceeds via an unprecedented dearomative activation mechanism.

Full text of DOI:10.1021/jacs.9b00210

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Communication
Glycosylation with 3,5-Dimethyl-4-(2’-phenylethynylphenyl)phenyl
(EPP) Glycosides via a Dearomative Activation Mechanism
Zhifei Hu, Yu Tang, and Biao Yu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b00210 • Publication Date (Web): 13 Mar 2019
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Journal of the American Chemical Society
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Glycosylation with 3,5-Dimethyl-4-(2’-phenylethynylphenyl)phenyl
(EPP) Glycosides via a Dearomative Activation Mechanism
Zhifei Hu,+& Yu Tang, ‡& Biao Yu‡*
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+ School of Physical Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China
‡ State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, China
Supporting Information Placeholder
and lactol 4 (43%). The phenanthrene derivative 3 was produced
apparently via an intramolecular Friedel-Crafts type of reaction
(Route 2). The presence of the hydrolyzed product 4 implied
generation of the glycosyl oxacarbenium species (I) and aglycone
derivative III in the reaction, that involved exactly the occurrence
of the expected glycosylation pathway (Route 1). To our surprise,
the aglycone derivative was determined to be spiroindene 5 rather
than the expected benzo[c]chromene III.7 Thus, a dearomative
pathway actually took place (Route 3).8 Such an activation mode
resulting in the cleavage of a O-glycoside is unprecedented.9
Herein, we disclose a new glycosylation protocol which capitalizes
on a relevant dearomative activation mechanism.
ABSTRACT: A highly effective and versatile glycosylation
method is developed, which uses 3,5-dimethyl-4-(2’-
phenylethynylphenyl)phenyl (EPP) glycosides as donors and
NIS/TMSOTf as promoter and proceeds via an unprecedented
dearomative activation mechanism.
The last decade witnesses the development of various new
glycosylation methods in efforts to tackle the challenges occurring
in the effective synthesis of glycans and glycoconjugates of great
structural diversity.1,2 A category of these reactions capitalizes on
selective activation of a C-C triple bond installed in the aglycone
of the glycosylation donors by alkynophilic reagents (Figure 1).3
Upon activation, the ester type donors (e.g., A4a and B4b) readily
undergo cleavage of the anomeric C-O bond, leading to the
glycosyl oxacarbenium related species (e.g., I) for glycosylation.1d
In comparison, the ether type donors (e.g., C5a) require much
stronger conditions for breaking of the glycosidic C-O bond, thus
limiting the scope of the resultant glycosylation reactions.
Nevertheless, the stability of the ether type donors would allow
various protecting group manipulations, thus to facilitate the
streamlined assembly of glycans and glycoconjugates (cf., the
versatility of thioglycosides in the synthesis of glycan).1b,6
Although we have disclosed that the glycosyl ortho-
alkynylbenzoates (B) are the optimal ester type donors under the
gold(I) catalysis,3a our efforts toward development of an ether type
donors basing on a similar activation mechanism met with no
success. We found both glycosyl ortho-alkynylbenzyl and ortho-
alkynylphenyl glycosides were inert toward gold(I) catalyst (e.g.,
Ph3PAuNTf2 and Ph3PAuOTf) under mild glycosylation
conditions. Further engineering of the aglycone led to ortho-
(methyltosylaminoethynyl)benzyl glycosides (D)5b and ortho-(p-
M+
M+
O
O+
O
HOR
O
O
O
O
OR
or
I
O
O
O
nBu
O
O
O
O
O
C
A
B
Hg2+
(Imagawa/Nishizawa, 2006)
Au+
(Yu, 2008)
Au3+
(Hotha, 2006)
O
Ts
N
This work
O
O
O
O
O
O
D
E
Me3Si+
(Yu, 2015)
I+
(Sun, 2017)
EPP Glycosides
Figure 1. The glycosylation protocols based on activation of C-C
triple bond and the representative glycosyl donors and promoters.
Bu = butyl, Ts = p-toluenesulfonyl.
methoxyphenylethynyl)phenyl
(MPEP)
glycosides
(E),5c
respectively. The former can undergo glycosylation under the
catalysis of TMSOTf more effectively than under Ph3PAuNTf2 or
Ph3PAuOTf, and the latter, remaining inert toward the gold(I)
catalyst, can be activated under NIS/TMSOTf to proceed
glycosylation.
To facilitate the dearomative pathway and for the reason of easy
preparation,
we
designed
3,5-dimethyl-4-(2’-
phenylethynylphenyl) phenyl (EPP) glycosides (9) as potential
glycosylation donors (Scheme 2). Compared to the original
biphenyl-2-yl glycoside 1, the new EPP glycosides are biphenyl-4-
yl glycosides, which are easier to synthesize, in addition, two
methyl substituents are introduced to avoid the competitive Friedel-
Crafts type of reaction. Indeed, an effective procedure was
developed for the synthesis of EPP glycosides, which generally
During the course of these studies, we once tried 2’-
(phenylethynyl)biphenyl glycoside 1 as a potential glycosylation
donor (Scheme 1). Glycoside 1 stayed inert in the presence of
Ph3PAuNTf2 or Ph3PAuOTf. Interestingly, it was converted under
the action of NIS/TMSOTf into phenanthrene glycoside 3 (37%)
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involved: (1) treatment of peracetyl monosaccharides (i.e., 6a-d)
and
1
2
3
4
5
6
7
BzO
BzO
BzO
NIS (2 eq), TMSOTf (0.2 eq),
BzO
BzO
BzO
O
BzO
BzO
BzO
CH2Cl2, -25 o
C
O
O
O
O
O
I
OH
OBz
+
+
OBz
I
OH
O
O
O
OBz
3
4
(43%)
(37%)
1
5 (58%)
O
O
Route 1
2a
Route 3
Route 2
I+
8
9
I+
I+
O
O
10
11
12
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O
O
O+
1
O
O
+
O
I
I
IV
V
II
III
Scheme 1. A proposed pathway for the glycosylation of 2’-(phenylethynyl)biphenyl glycoside 1 (Route 1) and the unexpected reactions
(Routes 2 and 3). Bz = benzoyl, NIS = N-iodosuccinimide, TMSOTf = trimethylsilyl trifluoromethanesulfonate.
I
2’-iodo-2,6-dimethyl-[1,1’-biphenyl]-4-ol (7; CCDC1882371)
with BF3·OEt2 or TMSOTf to give the corresponding phenyl
glycosides (8a-d) (71-86%); (2) protecting group transformation or
functional group conversion on the sugar unit; and (3) installation
of the phenylethynyl moiety on the aglycone via Sonagashira
coupling (86-97%).7 The resultant EPP glycosides (9a-h) are
crystalline compounds and stay inert on shelf for at least three
months. The structure of 9a was confirmed by X-ray diffraction
analysis (CCDC1881794).
I
HO
O
O
O
7
OAc
BF3.OEt2 (3.0 eq), NEt3 (1.0 eq),
or TMSOTf (1.5 eq), CH2Cl2, rt;
71-86%
(OAc)n
(OAc)n
8a-d
6a-d
EPP
O
Protecting group
manipulation
(see SI)
(Ph3P)2PdCl2 (0.15 eq),
CuI (0.5 eq), PPh3 (0.5 eq),
iPr2NH/DMF (2:1), 80 oC;
86-97%
O
Using perbenzoyl EPP glucopyranoside 9b as donor and methyl
2,3,6-tri-O-benzyl--glucopyranoside (2b),
a hindered sugar
P
(O
)
n
alcohol, as acceptor, we screened a series of promoters for the
glycosylation in CH2Cl2 at RT, to provide the coupled (1→4)-
disaccharide 10a.7 As expected, EPP glycoside 9b stayed inert in
the presence of Ph3PAuNTf2, Ph3PAuOTf, AuCl3, AgOTf,
TMSOTf, and HOTf, nevertheless, it underwent glycosylation
effectively under the action of NIS and TMSOTf.7 Where the
glycosylation took place, the spiroindene derivative 12 was readily
isolable, and its structure was confirmed unambiguously by X-ray
diffraction analysis (CCDC1881796)(Scheme 3).
9a-h
EPP
O
OR
O
O
O
RO
EPP
O
RO
EPP
O
RO
RO
RO
OR
OR
RO
OR
R = Ac/Bz
9a 9b 9c
9d 9e
/
/
/
R = Ac/Bz/Bn
R = Ac/Bz
BzO
9f 9g
/
EPP
O
O
BzO
OBz
9a
9h
Scheme 2. A general procedure for the preparation of EPP
glycosides and those studied in this report. Ac = acetyl, Bn =
benzyl.
The model glycosylation reaction (9b + 2b → 10a), employing
a disarmed donor and a hindered acceptor, could give the coupling
product in 90% yield under the action of NIS (1.5 eq) and TMSOTf
(0.3 eq) in CH2Cl2 at 0oC-RT. We were therefore confident that this
new glycosylation protocol would possess a wide reaction scope.
Indeed, under the present or slightly modified conditions, the
glycosylation of EPP donors (9a-9h) with a wide array of alcoholic
acceptors (2a-j)7 all led to the desired O-glycosides (10a-x) in
satisfactory yields (Scheme 3). Thus, employing perbenzoyl EPP
glucopyranoside 9b as donor, -(1→6)-, (1→2)-, (1→3)-, besides
the (1→4)-disaccharide, were synthesized in excellent yields (10a-
f; 85-98%); the glycosylation of aglycones, i.e., 1-adamantanol,
menthol, and benzyl oleanolate, provided the coupled glycosides
(10g-i) in ~90% yields. With perbenzyl EPP glucopyranoside (9c)
as donor, the glycosylation proceeded smoothly and led expectedly
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are known to be poor nucleophiles.11 To our good fortune, purines
to an anomeric mixture of the glycosides (10j-m, 87-96%, / =
1:3 to 2.2:1). The peracetyl EPP glucopyranoside (9a), like the
corresponding ortho-alkynylbenzoate,10 was a poor donor due to
formation of orthoester derived products. The peracetyl EPP
xylopyranosyl- and rhamnopyranosyl donors (9d and 9f) reacted
with the primary sugar alcohol 2b to give the desired glycosides
(10n and 10s) in ~70% yields along with by-products derived from
the donors;10 in comparison, their reactions with secondary
alcohols and the reactions of their perbenzoyl counterparts (9e and
9g) proceeded much cleanly, providing the corresponding coupled
glycosides (10o-q and 10t-x) in 84-98% yields. It is noteworthy
that the corresponding MPEP -rhamnopyranosides (E) did not
undergo glycosylation under the activation of NIS/TMSOTf.5c
1
2
3
4
5
6
7
8
(2o and 2p) were glycosylated with perbenzoyl EPP
glucopyranoside (9b) and ribofuranoside (9h) to give the desired
nucleosides (11d-f) in satisfactory yields (~70%). Upon activation
and solvation with BSTFA in CH3CN, pyrimidines (2m and 2n)
were glycosylated to provide the corresponding pyrimidine
nucleosides (11a-c) in excellent yields (>90%).
9
10
11
12
13
14
15
16
17
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The donor properties of the EPP glycosides were further tested
in the N-glycosylation of pyrimidine and purine derivatives, which
HOR 2a l
- ) or
Purine 2o 2p
( , ), 4Å MS,
a)
(
NIS (1.5 eq), TMSOTf (0.3 eq), CH2Cl2, 0 oC~RT
O
O
or
O
I
N
OR
+
or
=
O
O
Pyrimidine 2m 2n
) (2.0 eq), BSTFA (4.0 eq),
b)
(
,
P
(O
)
n
P
(O
)
n
P
(O
)
n
NIS (1.5 eq), TMSOTf (0.5 eq),
4Å MS, CH3CN, 0 oC~RT
9a-h
10a-x
11a-f
12
BzO
BzO
BzO
RO
RO
O
Ph
O
O
O
O
O
OBn
O
RO
RO
RO
O
BzO
BzO
BzO
O
O
AllO
O
RO
O
O
O
OR
BnO
BnO
OR
BzO
O
BzO
O
OMP
O
O
BzO
BzO
BnO
O
O
OBz
BzO
BnO
OBz
OMe
BzO
O
BnO
BzO
OMe
OMe
10e
(98%)
10d
10b (85%)
R = Bz (96%,  only)
R = Bn (89%, /=1.5:1)
10a
10c
(90%)
R = Bz (97%,  only)
R = Bn (87%, /=1:3)
c
c
10k
10j
Ph
O
O
O
O
RO
RO
RO
O
BzO
BzO
BzO
RO
O
H
COOBn
O
O
OBz
RO
RO
O
BzO
BzO
OR
H
BnO
O
OR
OBz
OMe
O
H
OBz
10g
10m
10f
10l
R = Bz (88%,  only)
R = Bn (96%, /=1.2:1)
R = Bz (95%,  only)
R = Bn (92%, /=2.2:1)
a
10h
(88%)
10i
(92%)
c
c
O
O
OAc
AcO
AcO
O
BzO
O
OBn
O
BzO
H
O
O
O
BzO
BzO
O
AcO
AcO
BzO
BzO
O
O
O
BnO
BnO
O
H
H
BnO
O
O
OAc
BnO
O
O
BnO
OMe
BzO
OBz
OBz
OMe
a
a
a
10n
(69%)
10o
10p
(99%)
(86%)
10q
(84%)
10r
(98%)
RO
O
OTBS
AcO
O
RO
RO
O
O
BzO
BzO
O
O
OBn
O
OBz
BzO
O
AcO
AcO
O
H
O
COOBn
BzO
BzO
BzO
BnO
BnO
O
O
O
O
O
BnO
H
O
O
O
O
BnO
BzO
BnO
OMe
O
OMe
BzO
H
a
10s
R = Ac (71%)
R = Bz (92%)
a
a
a
a
10x
(94%)
I
10u
10w
(98%)
(98%)
10v
(86%)
10t
NHBz
N
NBoc2
O
N
N
N
N
OBz
O
N
O
N
N
NH
N
OBz
O
NBoc2
BzO
BzO
BzO
NHBoc
N
N
N
O
BzO
N
O
NH
BzO
BzO
BzO
BzO
N
O
O
O
O
N
OBz
N
OBz
O
BzO
OBz
BzO OBz
11e
BzO
11c
BzO OBz
11b
OBz
b
11a
(92%)
11d
(69%)
b
b
(74%)
11f
(73%)
(90%)
(91%)
Scheme 3. Scope of the glycosylation reaction with EPP glycosides as donors under the action of NIS/TMSOTf. All = allyl, Boc = tert-
a
butoxycarbonyl, BSTFA = N,O-bis(trimethylsilyl)trifluoroacetamide, Ph = phenyl, TBS = tert-butyldimethylsilyl. The amount of TMSOTf
was increased to 0.5 equiv. bThe donor was used in excess (1.2 equiv) and the reaction performed at -20 oC-RT.cThe / ratio was determined
by 1H NMR analysis of the product mixture.
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OBz
O
OBn
O
Given the fact that the EPP donors are derived from the
BzO
BzO
BzO
O
BzO
BzO
STol
O
1
2
3
4
corresponding 2’-iodo-2,6-dimethylbiphenyl-4-yl glycosides (8),
which are inactive in the glycosylation conditions of the formers,
these donors could be applied to the expeditious synthesis of
glycans based on the ‘latent-active’ strategy.12 To prove the
BnO
OBz
OBz
BnO
OMe
(98%)
OBn
O
17a
(1.0 eq)
10a
(69%)
HO
BnO
17a
(93%)
+
+ 12
OBz
O
BnO
OMe
(1.0 eq)
concept,
2,3-di-O-benzoyl-4-O-benzyl-glucopyranoside
13,
BzO
BzO
OEPP
2b
5
6
7
8
readily prepared from peracetyl 2’-iodo-2,6-dimethylbiphenyl-4-yl
glycoside 8a via routine protecting group transformations (4 steps,
70% yield),7 was subjected to glycosylation with EPP xylosyl
donor 9e. Under the present glycosylation conditions, disaccharide
14 was obtained in an excellent 98% yield, which was then
converted readily into disaccharide EPP donor 15 via Sonagashira
coupling (94%). Subjection of the nascent donor 15 to the next
glycosylation with sugar alcohol 2b furnished trisaccharide 16
(85%).
OBz
OBn
NIS (1.0 eq), TMSOTf (0.3 eq),
4Å MS, CH2Cl2, -15~-5 C, 2h
BzO
BzO
BzO
O
O
9b
(1.0 eq)
O
BnO
OBz
BnO
OMe
OBn
O
10a
(67%)
BnO
BnO
STol
9
17b
(96%)
+
(94%)
+ 12
OBn
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
17b
(1.0 eq)
I
OH
O
HO
O
BzO
STol
BnO
BzO
O
BzO
OBz
OBz
13
O
I
I
BzO
BzO
18
(1.1 eq)
(1.0 eq)
OAc
O
OH
O
EPP
O
4 steps
70%
BnO
BzO
OBz
(1.25 eq)
AcO
AcO
O
O
NIS (1.25 eq), TMSOTf (0.3 eq),
4Å MS, CH2Cl2, 0C~RT, 2h
NIS (1.5 eq), TMSOTf (0.3 eq),
0 oC, 3h; 89%
9e
OBz
OAc
8a
13
O
BzO
O
O
BzO
BzO
O
O
O
BzO
BzO
I
BzO
BzO
EPP
O
BzO
I
O
BzO
OBz
BnO
OBz
O
O
BzO
BnO
BzO
9e
O
O
19
BzO
OBz
(Ph3P)2PdCl2 (0.15 eq),
CuI (0.5 eq), PPh3 (0.5 eq),
iPr2NH, DMF, 80 oC, 94%
NIS (1.5 eq), TMSOTf (0.3 eq),
4A MS, CH2Cl2, 0 oC-rt, 98%
OBz
14
Scheme 5. Comparison of the donor reactivity of the EPP
glycosides and thioglycosides under the action of NIS/TMSOTf
and a one-pot synthesis of trisaccharide 19.
OBn
O
O
BzO
O
O
BzO
BzO
O
HO
BnO
BzO
OBn
OBz
OBz
O
BnO
O
BnO
BzO
2b
O
OMe
O
BnO
BnO
EPP
O
BzO
BnO
OBz
NIS (1.5 eq), TMSOTf (0.3 eq),
4A MS, CH2Cl2, 0 oC-rt, 85%
OMe
In conclusion, we have developed a new glycosylation protocol
with EPP glycosides (9) as donors, which proceeds via an
unprecedented dearomative activation mechanism. This protocol,
which can proceed under mild conditions, has demonstrated a
broad reaction scope, including in the effective N-glycosylation of
nucleobases. The stability of the EPP glycosides and their
precursors allows various protecting group manipulations and
enables application in the streamlined synthesis of glycans and
glycoconjugates, as demonstrated here by the synthesis of
trisaccharide 16 with the latent-active strategy. In comparison to
the thioglycosides, which represent one of the most useful types of
glycosylation donors, the present EPP glycosides can be activated
much easily for glycosylation under the action of NIS/TMSOTf. In
fact, the combined use of EPP glycosides and thioglycosides has
demonstrated to be a new combination for one-pot synthesis of
glycans. More importantly, the aglycone transfer side reaction of
thioglycosides16 is completely avoided with the EPP donors, which
release spiroindene derivative 12 as an innocuous side product.
With these promising features, this new glycosylation method
deserves further studies and shall find wide application.
OBz
15
16
Scheme 4. A latent-active strategy for the synthesis of trisaccharide
16.
It is noted that the activation conditions (with NIS and TMSOTf
as promoter) for the present EPP glycosides have been effectively
applied for the glycosylation reactions with thioglycosides as
donors.6,13 Thus, we compared the donor reactivity of two pairs of
the EPP glycosides and thioglycosides (Scheme 5). In a mixture of
EPP and p-tolylthio perbenzoyl glucopyranoside (9b and 17a, 1.0
o
eq each) and sugar alcohol 2b (1.0 eq) in CH2Cl2 at -15 C were
added NIS (1.0 eq) and TMSOTf (0.3 eq). After 2 h, the EPP donor
9b was completely consumed, leading to the coupled disaccharide
10a and spiroindene derivative 12 in 69% and 93% isolated yield,
respectively; while the thioglycoside 17a was fully recovered
(98%). Moreover, in a similar competition reaction of EPP donor
9b and perbenzyl thioglycoside 17b, which is ~2000 times more
reactive than its perbenzoyl counterpart (17a),14 EPP donor 9b was
still the one being fully activated, leading to coupled disaccharide
10a (67%) and spiroindene 12 (96%), while the thioglycoside 17b
remained largely intact (94% recovery).15 This dramatic disparity
in reactivity would enable a one-pot synthesis of glycan with
combined use of an EPP donor and a thioglycoside acceptor
without a concern on the protecting group pattern.1b,6 To prove the
concept, EPP glycoside 9e was condensed with thioglycoside 18
under the action of NIS/TMSOTf to give the corresponding
thiodisaccharide, upon addition of acceptor 13 and another portion
of NIS/TMSOTf, the desired trisaccharide 19 was obtained in a
high 89% yield. Trisaccharide 19, which bears a 2’-iodo-2,6-
dimethylbiphenyl aglycone, could be further applied in the latent-
active synthesis (Scheme 5).
ASSOCIATED CONTENT
Supporting Information
Supporting Information. Experimental procedures, analytical data
(1H and 13C NMR, MS) for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
E-mail: byu@sioc.ac.cn
Author Contributions
& These authors contributed equally.
Notes
The authors declare no competing financial interests.
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(5) (a) Hotha, S.; Kashyap, S. Propargyl Glycosides as Stable Glycosyl
ACKNOWLEDGMENT
Donors: Anomeric Activation and Glycoside Syntheses. J. Am. Chem.
Soc. 2006, 128, 9620−9621. (b) Chen, X.; Shen, D.; Wang, Q.; Yang,
Y.; Yu, B. ortho-(Methyltosylaminoethynyl)benzyl Glycosides as
New Glycosyl Donors for Latent-Active Glycosylation. Chem.
Commun. 2015, 51, 13957−13960. (c) Hu, Y.; Yu, K.; Shi, L.-L.; Liu,
L.; Sui, J. -J.; Liu, D. -Y.; Xiong, B.; Sun, J. -S. o-(p-
1
2
3
4
5
6
7
8
Financial support from the National Key Research & Development
Program of China (2018YFA0507602), National Natural Science
Foundation of China (21432012, 21871290, and 21621002),
Strategic Priority Research Program of CAS (XDB20020000), K.
C. Wong Education Foundation, Shanghai Sailing Program
(17YF1424000), and China Postdoctoral Science Foundation
(2017LH038) is acknowledged.
Methoxyphenylethynyl)phenyl
Glycosides:
Versatile
New
Glycosylation Donors for the Highly Efficient Construction of
Glycosidic Linkages. J. Am. Chem. Soc. 2017, 139, 12736−12744.
(6) (a) Codée, J. D. C.; Litjens, R. E. J. N.; van den Bos, L. J.; Overkleeft,
H. S.; van der Marel, G. A. Thioglycosides in Sequential
Glycosylation Strategies. Chem. Soc. Rev. 2005, 34, 769–782. (b)
Lian, G.; Zhang, X.; Yu, B. Thioglycosides in Carbohydrate Research.
Carbohydr. Res. 2015, 403, 13–22.
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24.
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HOR
NIS, TMSOTf
O
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(OP)n
EPP Glycosides
I
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