Hydrogen-Bonding-Assisted Exogenous Nucleophilic Reagent Effect for β-Selective Glycosylation of Rare 3-Amino Sugars

Article abstract of DOI:10.1021/jacs.9b01862

Challenges for stereoselective glycosylation of deoxy sugars are notorious in carbohydrate chemistry. We herein report a novel strategy for the construction of the less investigated β-glycosidic bonds of 3,5-trans-3-amino-2,3,6-trideoxy sugars (3,5-trans-3-ADSs), which constitute the core structure of several biologically important antibiotics. Current protocol leverages a C-3 axial sulfonamide group in 3,5-trans-3-ADSs as a hydrogen-bond (H-bond) donor and repurposes substoichiometric phosphine oxide as an exogenous nucleophilic reagent (exNu) to establish an intramolecular H-bond between the former and the derived α-oxyphosphonium ion. This pivotal interaction stabilizes the α-face-covered intermediate to inhibit the formation of the more reactive β-intermediate, thereby yielding reversed β-selectivity, which is unconventional for an exNu-mediated glycosylation system. A wide range of substrates was accommodated, and good to excellent β-selectivities were ensured by this H-bonding-assisted exNu effect. The robustness of the current strategy was further attested by the architectural modification of natural products and drugs containing 3,5-trans-3-ADSs, as well as the synthesis of a trisaccharide unit in avidinorubicin.

Full text of DOI:10.1021/jacs.9b01862

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Article
Hydrogen Bonding Assisted Exogenous Nucleophilic Reagent
Effect for #-Selective Glycosylation of Rare 3-Amino Sugars
Jing Zeng, ruobin wang, Shuxin Zhang, Jing Fang, Shanshan Liu, Guangfei Sun,
Bingbing Xu, Ying Xiao, Dengxian Fu, Wenqi Zhang, Yixin Hu, and Qian Wan
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 08 May 2019
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Journal of the American Chemical Society
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Hydrogen Bonding Assisted Exogenous Nucleophilic Reagent Effect
for -Selective Glycosylation of Rare 3-Amino Sugars
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Jing Zeng,*,† Ruobin Wang,† Shuxin Zhang,† Jing Fang,† Shanshan Liu,‡ Guangfei Sun,† Bingbing Xu,†
Ying Xiao,† Dengxian Fu,† Wenqi Zhang,† Yixin Hu,† Qian Wan*,†,§
† Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Huazhong Univer-
sity of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China.
‡ The Institute for Advanced Studies, Wuhan University, 299 Bayi Street, Wuhan, Hubei, 430072, China.
§ Institute of Brain Research, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030,
China.
ABSTRACT: Challenges for stereoselective glycosylation of deoxy sugars are notorious in carbohydrate chemistry. We herein report
a novel strategy for the construction of the less investigated -glycosidic bonds of 3,5-trans-3-amino-2,3,6-trideoxysuars (3,5-trans-3-
ADSs) which constitute the core structure of several biologically-important antibiotics. Current protocol leverages a C-3 axial
sulfonamide group in 3,5-trans-3-ADSs as a hydrogen-bond (H-bond) donor and repurposes sub-stoichiometric of phosphine oxide
as exogenous nucleophilic reagent (exNu) to establish an intramolecular H-bond between the former and the derived -
oxyphosphonium ion. This pivotal interaction stabilizes the -face covered intermediate to inhibit the formation of the more reactive
-intermediate, thereby yielding reversed -selectivity which is unconventional for an exNu-mediated glycosylation system. Wide
range of substrates was accommodated and good to excellent -selectivities were insured by this H-bonding-assisted exNu effect.
The robustness of current strategy was further attested by the architectural modification of natural products and drugs containing 3,5-
trans-3-ADSs, as well as the synthesis of a trisaccharide unit in avidinorubicin.
a. Exogenous nucleophilic reagent (exNu) controlled -selectivity

INTRODUCTION
-covalent
-covalent
intermediates
intermediates
The construction of glycosidic bonds underpins the
development of carbohydrate chemistry. The structural
diversity and varying properties of mono- or oligosaccharides
render the stereoselective glycosylation an arduous task that
warrants intensive research efforts.1 Among them, one
appealing approach involves the application of exogenous
nucleophilic reagent (exNus) effect.2 While this strategy was
seminally reported in 1973,3 it has been recently revisited and
advanced by Mong4 and Codée,5 et al6 wherein screening of
various additives as modulators were mainly embodied in the
past decades (Scheme 1a). In general, these protocols
necessitate excess or even large excess of additives with
prevailing -selectivity.2 The -selectivity was deemed to be
engendered from the kinetically controlled -facial attack of
acceptors to the more reactive -covalent intermediate (C).
3-Amino-2,3,6-trideoxysugars (3-ADSs)7 belong to a more
rarely-encountered class of sugar, typically present in a few
anticancer drugs and antibiotics, for instance, saccharomicins,8
avidinorubicin,9 cororubicin10 and lobophorins.11 Significantly,
3-ADSs in these natural products commonly adopt the 3,5-trans
configuration and are consistently found to form -glycosidic
bonds with other sugars or aglycons. Chemical construction of
-O-glycosidic bonds in 3,5-trans-3-ADSs poses extra hurdles
due to the lack of C-2 participation group in addition to the
exceptional instability of the glycosidic bonds.12 The -
glycosidic bond was found susceptible to
O
O
exNu
O
O
exNu
ROH

OR
-glycosides
1
A
B
C
oxocarbenium
more stable
less active
less stable
more active
exNu: R2S, R2S=O, R3P, R3P=O, DMF related, etc.
b. Intramolecular H-bond in 3,5-trans-3-ADS
O
H+
O
AcO
AcO
72%,  > 20:1
NsN
O
OMe
(  2.7:1)
NsNH
H
H
2
3
X-Ray of
3
c. H-bond stabilized oxyphosphonium species for -glycosylation (this work)

-oxyphosphonium species

O
O
O
Au(I)
ROH
Ar3P=O
OABz
OR
NsN

Ar
O
Ar3P=O (4)
P
NsNH
H
NsNH
5
Ar
( 0.5 equiv)
trans
Ar
D
6
-glycosides
more stable, less active
higher selectivity
Ns
OABz
= alkynyl benzoate
= p-nitrobenzenesulfonyl;
hydrolysis or isomerization even under weakly acidic
conditions.7 Furthermore, although 1,3-diaxial effect exerted by
the C-3 axial substituents could promote the -selectivity, the
reversed selectivity was favored by anomeric effect, giving rise
to anomeric mixtures. Moreover, Finizia13 and Giuliano14
revealed that harnessing the C-3 anchimeric assistance might
not be necessarily helpful. Consequently, only two examples
Scheme 1. exNu effect for stereoselective glycosylation.
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a reduced loading of additive 4b to 0.5 equiv (1/3 equiv relative
featuring the stereoselective construction of -O-glycosidic
bonds of 3,5-trans-3-ADSs have been documented to-date, in
the independent works of McDonald15 and Bennett16 for the
synthesis of fragments of saccharomicins.17
1
2
3
4
5
6
7
8
to the donor) conserved the coupling yield and -selectivity
(entry 5). Also, Ph3PAuOTf catalyst provided coupling product
in lower yield and selectivity, while Ph3PAuBAr4F 23 exhibited
similar efficiency as Ph3PAuNTf2 (entries 7, 8). Further
In an earlier study on the diversified syntheses of 3,5-trans-
3-ADSs,7a an -hemiacetal 3 was obtained in excellent
selectivity when a methyl O-glycoside 2 was hydrolyzed under
acidic conditions. X-ray crystallography analysis revealed that
an intramolecular hydrogen-bond (H-bond) was formed
between the axial C-3 amide group and the oxygen atom of
anomeric hydroxy group, which could have bolstered the
formation of -anomer (Scheme 1b). This also hinted to the
efficacy of C-3 sulfonamide group as a good H-bond donor.18,19
Inspired by this observation, we envisioned that an
intramolecular H-bond could aid to stabilize -covalent
intermediate formed between an exNu and activated glycosyl
donor. With the assistance of this H-bond arose from the C-3
axial sulfonamide group, the formation of the corresponding -
covalent intermediate would be largely inhibited to restrict the
-facial attack on glycosyl acceptors. Eventually, glycosyl
acceptors could only approach from the -face thus deliver a
reversed stereo-outcome. Herein, we present our solution to
realize the challenging -selective glycosylation of 3,5-trans-3-
ADSs via a H-bond stabilized -oxyphosphonium intermediate
(D) by employing phosphine oxide as exNu (Scheme 1c).
Remarkably, only sub-stoichiometric amount of phosphine
oxide was required for current method.
F
investigations revealed that 0.05 equiv of Ph3PAuBAr4 was
sufficient to uphold the excellent stereoselectivity (entry 9). In
all cases, glycal 8 was identified to be the major byproduct.
Table 1. Optimization of reaction conditions.
9
OBn
10
11
12
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Ph3PAuNTf2 (0.2 equiv)
exNu (1.2 equiv)
OABz
+
OBn
O
NHNs
NsHN
O
HO
BnO
O
O
O
AcO
AcO
BnO
DCM (0.05 M), -40 o
C
BnO
BnO
OMe
5a
(1.5 equiv)
OMe
6a
7a
O
exNu
NHNs
O
P
O
F
P
3
O
MeO
Ph3P
O
Me
AcO
O
3
4c
4a
8
4b
OAbz
C5H11
Entry exNu
6aa
8c
:b
1
2
3
4
-
95%
95%
92%
75%
95%
97%
82%
96%
83%
1.6:1
15:1
28%
36%
36%
45%
35%
33%
45%
34%
20%
4a
4b
4c
4b
4b
4b
4b
4b
>20:1
4.8:1
>20:1
>20:1
8.7:1
>20:1
>20:1
5d
6e,f
7d,f
8d,g
9d,h
RESULTS AND DISCUSSION
a
b
Isolated yields;  to  ratio was determined by the yields of
Our studies commenced with screening of exNus (Table 1).
In our exploratory studies, it has been verified that the mild Yu
glycosylations20 could preserve both the sensitive glycosidic
bonds and high glycosylation efficiency. Using Au(I)-catalyzed
glycosylation of alkynyl benzoate donor 5a with 7a as model
reaction, disaccharide 6a was formed in excellent yield with
slight -selectivity in the absence of additive (entry 1). After
unsuccessful examination of several types of additives (see the
Supporting Information), we turned to phosphine oxides.
Mukaiyama and co-workers have elegantly introduced
phosphine oxides to modulate the -selectivity of common
sugars.21 Very recently, Codée et al. successfully employed this
strategy to assemble complex -glucans.5 To our delight,
significant increase in -selectivity was observed when the
additive was switched to triphenylphosphine oxide (TPPO, 4a)
(entry 2). The anomeric proton of -anomer exhibited as double
c
d
isolated anomers. Isolated yields based on 5a. 0.5 equiv of
e
additive (1/3 equiv related to the donor); solvent concentration
was 0.1 M; f Ph3PAuOTfwas used;g Ph3PAuBAr4F was used;h 0.05
F
F
equiv of Ph3PAuBAr4 was used. BAr4
= tetrakis[3,5-
bis(trifluoromethyl)phenyl]borate.
With these optimized conditions in hand, we then set out to
examine the scopes of the stereoselective glycosylation method
with Ph3PAuBAr4F as catalyst (Figure 1). As shown in Figure
1, four types of 3-ADS donors (5a-d) reacted well with various
acceptors to give products in good to excellent -selectivities.
The reaction with bulky primary alcohol furnished 6b in a /
ratio of 7.5:1, while the less sterically hindered and electron-
rich primary alcohols produced lower selectivity (6c). This
could be attributed to the secondary role of this glycosyl
acceptor as a good H-bond acceptor to compete with the
phosphine oxide additive. Correspondingly, an increased steric
hindrance or decreased acceptor reactivity could improve the
product selectivity, albeit with a compromised reaction yield
owing to the significantly temperate donor properties (6d). Acid
labile protecting groups such as benzylidene acetal and
isopropylidene acetal remained intact under the glycosylation
conditions (6b, 6e, 6f, 6h-k). In addition, thioglycosides were
well tolerated (6h-j), accentuating the potential of downstream
glycosylation by
1
doublet peaks with coupling constant of 9.6 and 2.4 Hz in H
NMR, indicating the equatorial orientation of the glycosidic
bond.22 Among the phosphine oxides surveyed, the electron rich
ones forged the glycosidic bond in excellent -selectivity.
Remarkably, -isomer was exclusively isolated when 4b was
used as an additive due to its increased nucleophilicity (entry
3). In contrast, electron deficient phosphine oxide (4c, entry 4)
displayed lower reaction efficiency but yielded a much higher
selectivity than the control experiment (entry 1). Interestingly,
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Ph3PAuBAr4F (0.1 equiv)
NsHN
1
2
3
4b
(0.5 equiv)
5a d
-
R-OH
+
O
OR
4 Å MS, DCM, -40 °C
(1.5 equiv)
7
6
4
5
6
7
OABz
OABz
NsHN
Me
O
NsHN
O
AcO
Me
AcO
NsHN
S
O
O
AcO
AcO
O
OABz
OABz
NsHN
5a
5c
5d
5b
OPTB
8
9
from natural products and drugs
from 5a
O
O
O
10
11
12
13
14
15
16
17
18
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20
21
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OBn
O
NsHN
O
O
O
BnO
O
O
O
O
O
AcO
O
BnO
BnO
O
BnO
O
BnO
O
OMe
OMe
O
H
H
6db
38%,  only
6c
H
6b
O
H
H
NsHN
94%, : = 3.8:1
H
95%, : = 7.5:1
O
O
AcO
diosgenin
from
6ne
O
O
Ph
O
Ph
O
O
O
O
O
, 95%, : = 4.2:1
AcO
O
simvastatin
from
O
AcO
CbzHN
OMe
6md
OMe
OMe
, 83%, : = 9:1
OMe
6e
80%,  only
6g
75%, : = 6:1
OMe
MeO
6f
O
O
82%,  only
OAc
CH3
O
O
O
O
from 5b-5d
H3C
STol
R''
O
O
AcO
OH
O
O
O
AcO
O
Me
O
O
O
AcO
AcO
O
O
O
O
H
NHNs
from
O
NHNs
digoxigenin
from
podophyllotoxin
NHNs
NHNs
6pc,d
rha-sac disaccharide
of saccharomicins
6o
, 83%, : = 5:1
, 70%,  only
6h
6i
, R'' = OPTB, 85%, : = 7.5:1
, R'' = STol, 95%, : = 9:1
6j
, 88%,  only
R
O
O
OH
OH
O
OMe
Ph
O
O
AcO
Me
O
R
O
O
O
AcO
O
O
O
NsHN
HO
O
NsHN
AcO
OMe
O
O
O
NsHN
AcO
O
NsHN
6rc,e
O
O
AcO
O
6k
, 95%, : = 8:1
6qc,e
NHNs
daunorubicin
from
, 83%, : = 3.5:1
, 85%, : = 8:1
6lc
, 68%,  only
Figure 1. Substrate scope.a a Unless otherwise specified, the yields were isolated yields, the / ratios were determined by the isolated
isomers separated by column chromatography on silica gel. b Donor (1.0 equiv), acceptor (2.0 equiv), Au(I) cat. (0.07 equiv). cDonor (3.0
equiv), 4b (1.0 equiv). d 4a (0.5 equiv) was used instead of 4b. e 0.2 equiv of Au(I) cat. was used.
activation of thioglycosides (6i, 6j), or the employment of an
interrupted Pummerer reaction-mediated (IPRm) glycosylation
strategy (6h).24 Encouraged by these observations, we also
synthesized the Rha-Sac disaccharide unit (6j) of
saccharomicins. Coupling of two molecules of 3-ADS donors
with an acceptor possessing two free hydroxy groups
maintained a satisfactory yield of 68% of 6l as a single isomer.
These successes stimulated us to further extend this strategy
to the modification of natural products and drugs containing 3-
ADSs skeleton (Figure 1). Among the tested natural products
and drugs, glycosylation of simvastatin with 5a offered 6m in
83% yield with  to  ratio of 9:1. For chemical modification
of podophyllotoxin which constitutes the key pharmacophore of
several clinical antitumoral agents,25 the construction of
aryltetralin 4-O-glycosidic linkages was conventionally
stymied by the high lability of the podophyllotoxin structure
towards both acidic and basic conditions.26 With our method,
the coupling of podophyllotoxin with 5c provided 6p as a sole
anomer in high efficiency by application of the established H-
bonding assisted exNu effect. It should be noted that TPPO (4a)
was used instead of 4b in the preparation of 6m and 6p, which
otherwise gave rise to extremely low product yields. Our next
target was steroid which offer broad-range bioactivities and
which the activity profiles vary with the modifications on sugar
moieties. We have previously demonstrated the glycosylation
of diosgenin and digoxigenin with 3-ADSs in an -favored
selectivity.7b,c With the present method, we successfully
assembled glycosylated diosgenin 6n and digoxigenin 6o in
good -selectivity. Aside from that, anthracyclines possessing
3-ADSs moiety have been widely used for cancer therapy. Of
note, Wang and Sun et al have proven that modification of the
sugar moieties could augment their antitumor activity and
overcome the drug resistance.27 Without much hurdles, current
method facilely delivered the -3-ADS analogues of
anthracyclines (6q, 6r) in high efficiency. Interestingly, a chiral
discrimination was observed in this case: L-3-ADS (6q) was
formed in superior selectivity than D-3-ADS (6r).
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Encouraged by the high efficiency of this strategy, we
which was attached to the aminosugars with -orientation. With
the phosphine oxide-mediated -glycosylation strategy, the
1
2
3
4
5
6
7
8
proceeded with its employment in the assembly of
oligosaccharides (Scheme 2). We were interested to elaborate a
diol acceptor 10 with both  and  linkages. Employing
Mukaiyama’s -glycosylation protocol20 with TMSI as
activator and excess TPPO (4a) as additive, disaccharide 11 was
selectively obtained in 61% yield with  to  ratio of 16.5:1.
Subsequently, with the same additive 4a but in sub-
stoichiometric amount, the coupling reaction between 11 and 5c
successfully constructed the -glycosidic bond and the
trisaccharide 12 was isolated as a single isomer in 68% yield
(80% brsm). This result clearly demonstrated that H-bonding
effect participated in the reversion of the selectivity. Given the
robustness of gold-catalyzed Yu glycosylation reaction and
excellent stereo-control of present methodology, we then
contemplated a one-pot synthesis of trisaccharide 15 with
coupling of 3-ADSs 5b and 16 furnished disaccharide 17 in 66%
yield with absolute -stereoselective control. Subsequent
deprotection of the acetate group produced 18 in 93% yield. The
X-ray crystallography analysis of 18 confirmed the -linkage.
Finally, subjecting 2,6-dideoxy sugar 19 and disaccharide 18 to
Yu glycosylation conditions successfully constructed the
protected trisaccharide unit of avidinorubicin 20 in satisfactory
reaction outcome.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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36
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41
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60
Scheme 3. Synthesis of trisaccharide unit of avidinorubicin.
HO
Me2N
NH2
OH
NH2
O
O

O
OH
O
O
F
O
O
O
Ph3PAuBAr4 as the single catalyst. We envisaged that the
O
Me
Me
coupling reaction between 13 and 14 would occur site-
selectively in the presence of gold catalyst on O-6 position of
diol 14 with -selectivity. The ensuing addition of 5a and 0.5
equiv of phosphine oxide 4b into the resulting mixture would
then promote the introduction of 3-ADS on O-4 position with
-orientation. Pleasingly, this two-step one-pot protocol
auspiciously produced the trisaccharide 15 in 52% overall yield
with absolute stereocontrol. The reaction also showed good
compatibility with S-2-[(propan-2-yl)sulfinyl]benzyl (SPTB)
glycosides,28 thus bodes well for IPRm glycosylation to
elongate the sugar chains.

O
O
OH
MeO
O
COOH
O
avidinorubicin
NMe2
O
HO
OMe
PPh3AuNTf2
OABz
NsHN
Me
OMe
NsHN
Me

NsHN
NsHN
Me
4a
(0.5 equiv)
O
O
O
O
O
+
AcO
HO
AcO
66%,  only
Me
5b
16
17
K2CO3
MeOH
93%
OMe
NsHN

NsHN
O
O
O
Scheme 2. Assembly of trisaccharides.
HO
Me
Me
18
(a)
BnO
BnO
BnO
OMe
+
NsHN

NsHN
HO
HO
BnO
I
TMS (1.2 equiv)
BnO
BnO
BnO
O
O
4a
O
(3.0 equiv)
O
O

O
+
OABz
Ph3PAuNTf2
DCM, -40 °C
O
O
OAc
BnO
Me
DCM, rt
Me
O
BnO
BnO
OAc
OMe
:
16.5:1
61%,  
O
AcO

O
HO
BnO
11
20
10
9
(1.2 equiv)
19
86%,

only
avidinorubicin
trisaccharide
OAc
BnO
AcO
BnO
BnO
BnO
OMe
5c
(3.0 equiv)
Ph3PAuBAr4F (0.2 equiv)
4a
O

Table 2. Selectivity variations by modification of the amide
group
BnO
(0.5 equiv)
DCM, -40 °C to -20 °C
only
O
O
O
O
BnO
AcO
68% (80% brsm), 

BnO
NHNs
OH
OMe
12
O
Ph3PAuBAr4F (0.2 equiv)
OABz
RHN
O
RHN
5
4b (0.5 equiv)
O
(b)
OAc
O
+
O
O
AcO
F
AcO
O
DCM, -40 o
C
1). Ph3PAuBAr4
(0.3 equiv)
O
O
OAc
HO
BnO
AcO
7b
6

O
O
SPTB
OABz
HO
AcO
DCM, -78 °C
O
BnO
HO
BnO
O
SPTB
13
14
OBn
Yield, :
OAc
O
Entry
R
5a 4b
,
2).
(0.5 equiv)
AcO

with 4b
w/o 4b
S
O
-40 °C to -20 °C
NsHN
O
BnO
S
SPTB
two steps in one-pot
one catalyst
1
2
3
4
Ns (5a)
Ts (5e)
Ms (5f)
6b, 95%, 7.5:1
6s, 96%, 3.7:1
6t, 92%, 3.9:1
6u, 95%, 6.3:1
97%, 1.5:1
95%, 1.5:1
95%, 1.5:1
96%, 3.9:1
O
O
AcO

OBn
SPTB
52%
15
CF3CO (5g)
This -selective glycosylation methodology was further
utilized to the construction of trisaccharide unit of
avidinorubicin (Scheme 3). Avidinorubicin which was isolated
from the cultured broth of Streptomyces avidinii in 1991,
exhibited platelet aggregation inhibitory activity.9 It was also
recognized as the conceivable biosynthetic precursor of an
antitumor antibiotic, decilorubicin.29 The structure complexity
of avidinorubicin poses great synthetic challenge, and report of
its synthesis is long overdue. The terminal trisaccharide unit of
avidinorubicin contains two continuous 3-branched 3,5-trans-
3-ADSs linked with -glycosidic bond, and a 2,6-dideoxysugar
The high efficacy of the phosphine oxide-mediated
stereoselective glycosylation prompted us to verify the
existence of the H-bonding effect by probing the relationship
between the selectivity outcome and the H-bond donation
capacity of the C-3 amide group (Table 2). A series of 3-ADS
donors (5a, 5e-g) possessing different C-3 amide groups were
coupled with 7b in the presence of 4b. The selectivity declined
significantly from 7.5:1 to 3.7:1 ( to ) as expected, when the
Ns group was replaced by the less electron-deficient p-
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toluenesufonyl (Ts, 5e) group which diminished the H-bond
covered oxyphosphonium intermediate and prevented the
formation of the corresponding -intermediate. This primes the
-face for glycosyl acceptors for intended -selectivity.
Notably, unlike the known exNu reagent effect-mediated
glycosylations, only sub-stoichiometric amount of phosphine
oxide was required in current protocol. Wide range of substrates
including natural products and drugs containing variegated
functionalities were well tolerated. In particular, the
orthogonality of the present strategy toward the thioglycoside
activation method and the IPRm glycosylation method pointed
up its vast potential in the assembly of complex
oligosaccharides. This strategy offered an expedient solution
for the challenging -selective glycosylation of 3,5-trans-3-
ADSs and paved the way to the synthesis as well as the
modification of 3,5-trans-3-ADS-containing naturally
occurring oligosaccharides and glycoconjugates.
1
2
3
4
5
6
7
8
donation ability of the amide group (entry 2). Switching the N-
protecting group to methansulfonyl group (Ms, 5g) that presents
lower steric encumbrance but higher pKa value as compared to
Ns group, also resulted in the erosion of the stereoselectivity
(entry 3). When phosphine oxide 4b was excluded in all these
cases, the selectivity was lost. These results vigorously implied
that the -selectivity arose from the -face shielded H-bonding
between the amide group and -oxyphosphonium ion.
Interestingly, in contrast to the observations of Finizia13 and
Giuliano,14 an improved -selectivity was observed with
trifluoroacetate as N-protecting group (5g) when no additive
was present (entry4). This implied the plausible existence of a
weak C-3 anchimeric assistance. Accordingly, the addition of
phosphine oxide further increased the selectivity in this case.
Next, the selectivity variations were observed by disruption
of the H-bonding (Scheme 4). First, when the hydrogen atom
of 4-nitrobenzensulfonylamide was replaced by a methyl group,
9
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
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ASSOCIATED CONTENT
Supporting Information
1
4
the conformation of the donor (5h) flipped from C4 to C1,
possibly due to an increased 1,3-diaxial effect. The coupling
reaction between the flipped 5h and 7a catalyzed by
Ph3PAuNTf2 furnished 6v and 6v in a ratio of 1.25:1, in the
absence of additive. Similarly, conformation of the -product
6v also flipped to 4C1 while the conformation of -anomer was
generally retained as 1C4 with slight twist. These conformations
were confirmed by both the coupling constants of the anomeric
proton and the X-ray crystallography analysis (see the
supporting information).30 Interestingly, the addition of
triphenylphosphine oxide (TPPO, 4a) as additive increased the
-selectivity. Since bulkier protecting group might lead to
conformation changes, we then considered the installation of
azide group on C-3 position of the donor. Unlike the above-
mentioned amido donors (5a and 5e-h), replacement of the
amide group with azide group resulted in the formation of the
glycosyl donor 5i as a -anomer, pertaining to the absence of
H-bond. The -selectivity of the coupling reaction of 5i was
increased in the presence of phosphine oxide, similar to the
conventional exNu effect-assisted glycosylations. These results
further conformed to the central role of H-bond-assisted exNu
effect in imparting -selectivity.31
The supporting Information is available free of charge via the
Internet at http://pubs.acs.org.
Experimental procedures, crystal structures, spectroscopic and
analytical data for all compounds (PDF)
Crystallographic data for 3 (CIF)
Crystallographic data for 6v (CIF)
Crystallographic data for S8 (CIF)
Crystallographic data for 18 (CIF)
AUTHOR INFORMATION
Corresponding Author
*zengjing0052@hust.edu.cn
*wanqian@hust.edu.cn
ORCID
Jing Zeng: 0000-0001-9116-9861
Qian Wan: 0000-0001-9243-8939
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Scheme 4. Glycosylations without H-bonding.
We greatly appreciated the financial support from National Natural
Science Foundation of China (21772050, 21672077,
21761132014), the State Key Laboratory of Bio-organic and
Natural Products Chemistry (SKLBNPC13425), Wuhan Creative
Talent Development Fund, the Fundamental Research Funds for
the Central Universities (2016YXMS137). We thank Analytical
and Testing Center of HUST for X-ray and NMR tests. We also
thank Dr. Huping Zhu from Shanghai Institute of Organic
Chemistry for help on low temperature NMR spectroscopy studies.
OAc
Me
7a, Ph3PAuNTf2 (0.2 equiv)
OAc
O
NNs
OABz
O
NsN
Me
+
O
O
NsN
Me
O
4a
w/o , 95%,   1.25:1
AcO
4a
w
, 80%,   1:3.6
5h
6v

6v

7b, Ph3PAuBAr4F (0.2 equiv)
N3
O
N3
O
N3
O
OABz
O
+
AcO
O
AcO
4b
w/o , 95%,   1:1.4
AcO
5i
4b
w
, 95%,   1:2.9
6w

6w

Conclusion
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(30) CCDC 1889014 (3), 1889018 (18), 1889013 (6v) and 1889006 (S8)
contain the supplementary crystallographic data for this paper. These data
are provided free of charge by The Cambridge Crystallographic Data
Centre.
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(31) Although it is difficult to confirm the exact structure of the proposed
glycosyl oxyphosphonium ion intermediate through low-temperature NMR
spectroscopy studies at this stage, several weak signals possibly attributed
to the interactions between the P atom to the anomeric proton and the P
1
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details, see the Supporting Information. For NMR studies on glycosyl
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Salts as Effective Reagents for Stereoselective Synthesis of 1,2-cis-
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BnO
BnO
BnO
BnO
BnO
BnO
O
Ar
O

P
Ar
Ar
O
:
16.5:1
only

 
BnO
O
O
BnO
O
BnO
O
O
O
BnO
AcO
O
HO
BnO

BnO
more reactive
-oxyphosphonium
NHNs
OMe
BnO

OMe
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Au (I)
Ar3P=O
(0.16 equiv)
O
O
AcO
NsN
AcO
-Glycosylation of 3-amino sugars
Ar
H-bonding assisted exogenous

O
P
Ar
Ar
OAbz
NsNH
H
nucleophilic reagent effect
Reversal of selectivity
Substoichiometric amount of additive


H-bond stabilized
-oxyphosphonium

8
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