Directing effect by remote electron-withdrawing protecting groups at O-3 or O-4 position of donors in glucosylations and galactosylations

Article abstract of DOI:10.1016/j.tet.2015.06.014

Glucosylations and galactosylations of various acceptors with donors possessing an electron-withdrawing benzylsulfonyl, benzoyl, or acetyl group at the O-3 or O-4 position were performed. A β-directing effect by the benzylsulfonyl group at O-3 of the glucosyl donors and by the benzylsulfonyl and acyl groups at O-4 of the glucosyl donors was observed. In contrast, acyl groups at O-3 of the glucosyl donors and acyl groups at O-3 and O-4 of the galactosyl donors exhibited an α-directing effect. The α-directing effect is partly considered to remote participation of the acyl groups, whereas the β-directing effect is somewhat attributed to the S_N2-like reaction of the acceptor with the glycosyl triflate or the contact ion pair, which is stabilized by remote electron-withdrawing groups. Further evidence for the stability of the α-glycosyl triflates was determined by a low-temperature NMR study.

Full text of DOI:10.1016/j.tet.2015.06.014

Tetrahedron 71 (2015) 5315e5320
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Directing effect by remote electron-withdrawing protecting groups
at O-3 or O-4 position of donors in glucosylations and
galactosylations
Ju Yuel Baek c d, Hea-Won Kwon a, Se Jin Myung a, Jung Jun Park a, Mi Young Kim a,
,
,
,
c
,
d,
a,
*
Dominea C.K. Rathwell c d, Heung Bae Jeon b , Peter H. Seeberger
, Kwan Soo Kim
*
*
a Center for Bioactive Molecular Hybrids and Department of Chemistry, Yonsei University, Seoul 120-749, Republic of Korea
b Department of Chemistry, Kwangwoon University, Seoul 139-701, Republic of Korea
c
€
Max Planck Institute of Colloids and Interfaces, Am Muhlenberg 1, 14424 Posdam, Germany
d
€
Institute of Chemistry and Biochemistry, Freie Universitat Berlin, Arnimallee 22, 14195 Berlin, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Glucosylations and galactosylations of various acceptors with donors possessing an electron-
withdrawing benzylsulfonyl, benzoyl, or acetyl group at the O-3 or O-4 position were performed. A
directing effect by the benzylsulfonyl group at O-3 of the glucosyl donors and by the benzylsulfonyl and
acyl groups at O-4 of the glucosyl donors was observed. In contrast, acyl groups at O-3 of the glucosyl
Received 17 April 2015
Received in revised form 2 June 2015
Accepted 3 June 2015
b-
Available online 10 June 2015
donors and acyl groups at O-3 and O-4 of the galactosyl donors exhibited an
a
-directing effect. The
a-
directing effect is partly considered to remote participation of the acyl groups, whereas the
effect is somewhat attributed to the SN2-like reaction of the acceptor with the glycosyl triflate or the
contact ion pair, which is stabilized by remote electron-withdrawing groups. Further evidence for the
b
-directing
Keywords:
a
a
-Selective glucosylation
-Selective galactosylation
stability of the
a-glycosyl triflates was determined by a low-temperature NMR study.
Electron-withdrawing protecting groups
Remote participation
Ó 2015 Elsevier Ltd. All rights reserved.
a
-Glycosyl triflates
1. Introduction
Interestingly, the conceptually simple extension of the reliable
and well established O-2 neighboring group assistance approach to
the more remote positions of O-3 and O-4 in glycosyl donors to
explore their effect on the stereochemical outcome of glycosylation
has been mired in controversy.7 In particular, the possibility of re-
mote protecting group participation on the equatorial O-3 and axial
O-4 positions of the glycosyl donors is a highly debated. Crich et al.
There has been intense interest in the development of stereo-
selective glycosylation methodologies in the past decade, which
has been driven by the emerging importance of the roles that
complex carbohydrates play in many biological processes.1 The
stereoselectivity of glycosylation reactions is governed by numer-
ous factors such as the leaving group, the protecting groups, and the
nature of the activation system as well as the solvents. The effect of
protecting groups on selectivity is well understood; in fact, 2-O-
carboxylate ester mediated neighboring group participation is one
of the most established approaches to reliably constructing 1,2-
trans-glycosidic linkages.2 In contrast, the stereoselective con-
has conducted
a trapping experiment using the tert-butox-
ycarbonyl ester and concluded that the neighboring group partic-
ipation does not occur under typical glycosylation conditions in
donors with acyl protecting groups at the O-3-equatorial, both the
O-4-axial and O-4-equatorial, and the O-6 positions, because no
participation intermediates could be isolated.8 Additionally, while
struction of the 1,2-cis-glycosidic linkage of
a
-glucoside and
a
-ga-
observing high a-selectivities in glucosylation with donors bearing
lactoside remains one of the great challenges for carbohydrate
chemists, because the classical method utilizing 2-O-acyl-protect-
ing group participation is not possible.3 Several innovative strate-
acyl groups at the O-3 position, van Boeckel et al. argued against
ascribing remote participation to the observed selectivity as the
comparable level of
a-selectivity was observed with a 3-O-tri-
gies for
a
-selective glucosylation and galactosylation have been
chloroacetyl protecting group on the donor, which they assumed to
be non-participating.9 Nevertheless, results and evidence in favor
of remote participation in the glycosylations of glucosyl, galactosyl
developed, including an indirect intramolecular approach4 or
a hydrogen-bond5 mediated aglycon delivery approach, and the use
of chiral auxiliaries.6
and related donors are quite substantial.7a,10 High
a-selectivity was
reported for glycosylations with glucosyl donors bearing an acyl
* Corresponding authors. E-mail addresses: hbj@kw.ac.kr (H.B. Jeon), Peter.
seeberger@mpikg.mpg.de (P.H. Seeberger), kwan@yonsei.ac.kr (K.S. Kim).
protecting group at the O-3 or O-6 position11 and
http://dx.doi.org/10.1016/j.tet.2015.06.014
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

5316
J.Y. Baek et al. / Tetrahedron 71 (2015) 5315e5320
a diethylthiocarbamoyl group at the O-6 position.12 For gal-
actosylations with donors possessing the acyl13 or diethylth-
iocarbamoyl12 groups as potential participating groups at O-4, high
O-4 positions (see Supplementary data). The standard donors
bearing no electron-withdrawing groups (tetra-O-benzyl-glucosyl
donor 4 and tetra-O-benzyl-galactosyl donor 11) were also pre-
pared. By comparing the glycosylation stereochemistry resulting
from the standard donors, which were the donors bearing non-
participatory electron-withdrawing protecting groups (SO2Bn),
and the electron-withdrawing group protecting groups that are
potential participators (acyl protecting groups), we aimed to dif-
ferentiate between the electron-withdrawing group effect and the
remote participation effect by remote electron-withdrawing pro-
tecting groups.
to moderate
for galactosylation with a galactosyl donor possessing an acetyl
group at O-6, resulting in moderate
-selectivity.14 Furthermore,
a-selectivities were reported. There was also a report
a
the combination of two potential participating benzoyl groups at
the O-4 and O-6 positions15 or acetyl groups at the O-3 and O-4
positions16 in galactosyl donors was reported to induce high
a
-se-
lectivity. Glycosylations with 2-azidogalactosyl donors possessing
two acetyl groups at the O-3 and O-4 positions yielded high -se-
a
lectivity and the proposed remote protecting group effect of the
acetyl group was supported by computational work on supposed
participation intermediates.17 Recently, the remote participation of
the 4-O-acetyl group in a glucosyl donor was corroborated by iso-
lation of an 1,2,4-O-orthoester.18
Admittedly, the comparison of such results is not a straightfor-
ward task as the reaction outcomes may be influenced by slight
changes in the reaction conditions for a given acceptor/donor pair.
Differences in leaving groups, promoters, temperature and solvents
can all affect the outcome. Thus, a careful systematic study on the
effect of the electron-withdrawing protecting groups and the po-
tential remote participation of these protecting groups on the O-3
and O-4 positions of glucosyl and galactosyl donors should be
conducted to allow for better comparison. Previous work in our
group methodically explored the effect of electron-withdrawing
protecting groups in mannosyl donors on the stereoselective out-
come of mannosylations.19 Our results from these mannosylations
Primary hydroxy sugars 15, 16 and 17 and secondary hydroxy
sugars 18 and 19 were chosen as acceptors, as shown in Fig. 2. With
the sets of glycosyl donors and acceptors in hand, glycosylation was
carried out in the following pre-activated one-pot sequence: (i)
a solution of the glycosyl donor (1.0 equiv) and 1-benzenesulfinyl
piperidine (BSP, 1.2 equiv) was stirred in CH2Cl2 in the presence
ꢀ
of 4 A molecular sieves for 15 min at room temperature and cooled
to ꢀ60 ꢁC; (ii) Tf2O (1.2 equiv) was then added to this solution at
ꢀ60 ꢁC and stirred for an additional 10 min; and (iii) a solution of
the glycosyl acceptor (1.5 equiv) and 2,4,6-tri-tert-butylpyridine
(TTBP, 2.0 equiv) was added at ꢀ60 ꢁC, stirred for 20 min, and
allowed to warm to 0 ꢁC over 1 h. The reaction was quenched with
saturated aqueous NaHCO3 at 0 ꢁC. We observed no anomerization
of the products under the present glycosylation conditions. With-
out TTBP, the anomeric ratios of the product glycosides in certain
cases were slightly different from those of the products obtained in
the presence of TTBP.
showed b-directing effects in the glycosylations with the donors
bearing strong electron-withdrawing groups (EWGs; i.e., SO2Bn) at
the O-3 or O-4 position, which we attributed to the shift in equi-
2.2. Glucosylations with donors possessing an electron-
withdrawing group at O-3
librium toward
intermediates.19 Potential participating groups such as the acyl
groups on O-3 and the acetyl group on O-6 of the donors had an
a-triflate intermediates from oxocarbenium ion
In the glucosylations of primary alcohol acceptors 15, 16, and 17
with glucosyl donor 1 bearing a non-participating benzylsulfonyl
a
-
directing effect in the mannosylations. This observation was as-
cribed to the remote participation of the acyl group through diox-
ocarbenium ion intermediates. Expounding upon previous work,
this current report systematically investigates how the electron-
withdrawing effects and the potential participation of protecting
groups at the remote O-3 and O-4 positions of glucosyl and galac-
tosyl donors affects the anomeric selectivity. Furthermore, low-
temperature NMR study was performed to investigate the stabil-
group at O-3,
withdrawing SO2Bn group were observed (entries 1 (
5 ( ¼1/7.3) in Table 1). In the glucosylations of
¼1/1.8), and 9 (
more sterically demanding secondary alcohol acceptors 18 and 19
with donor 1, no -directing effect was seen (entries 13 and 17 in
Table 1). With glucosyl donors 2 and 3 carrying an acyl protecting
group at the O-3 position, -selectivities were observed in the
glucosylations of secondary alcohol acceptors 18 and 19, yielding
disaccharides 33 (EWG¼Bz, ¼4.0/1), 34 (EWG¼Ac, ¼4.0/1),
37 (EWG¼Bz, only), and 38 (EWG¼Ac, only), respectively, with
an excess of -anomers (entries 14, 15, 18, and 19 in Table 1). We
ascribe the observed -directing selectivity to the remote partici-
pation by the acyl protecting group. However, the -directing effect
b
-directing effects by the strongly electron-
a/b¼1/4.3),
a
/b
a/b
b
a
ity of
-directing effect of non-participating electron-withdrawing group
a
-glycosyl triflate intermediates,20 which seems to induce the
a
/b
a/b
b
a
a
a
of O-3 and O-4 positions of glycosyl donors.
a
2. Results and discussion
a
by acyl groups was not clearly shown in glucosylations of primary
2.1. Synthesis of glycosyl donors and glycosylation conditions
alcohol acceptors, 15, 16, and 17 with glucosyl donors 2 and 3
(entries 2, 3, 6, 7, 10, and 11 in Table 1). The diminished
1.9/1e1/1.9, observed in the glucosylation of the primary alcohol
acceptors compared with the secondary alcohol acceptors ( ra-
tios: 4.0/1e only) with donors 2 and 3 bearing an acyl group at the
O-3 position might be due to the -directing effect by the electron
a/b ratios,
Glucosyl and galactosyl donors 1e3, 5e10, and 12e14 were
prepared, as shown in Fig. 1, bearing either a non-participating
strong electron-withdrawing group (SO2Bn) or a potentially par-
ticipating weak electron-withdrawing group (Bz, Ac) at the O-3 and
a/b
a
b
Fig. 1. Thioglucosyl and thiogalactosyl donors 1e14.

J.Y. Baek et al. / Tetrahedron 71 (2015) 5315e5320
5317
Fig. 2. List of glycosyl acceptors 15e19.
Table 1
Glucosylations with donors 1e3 having an EWG at the O-3 position
Table 2
Glucosylations with donors 5e7 having an EWG at the O-4 position
Product (yield,%)a
Ratiob
(a/b)
Entry
ROH
Donor
EWG
Product (yield,%)a
Ratiob
(a/b)
Entry
ROH
Donor
EWG
1
2
3
4
5
6
7
8
15
5
6
7
4
5
6
7
4
5
6
7
4
5
6
7
4
5
6
7
4
SO2Bn
Bz
40 (90)
41 (84)
42 (88)
23 (89)
43 (82)
44 (80)
45 (85)
27 (81)
46 (79)
47 (89)
48 (76)
31 (89)
49 (80)
50 (75)
51 (76)
35 (79)
52 (84)
53 (84)
54 (80)
39 (92)
1/5.7
1/4.9
1/2.8
1/1.9
1/2.0
1/3.0
1/1
1
2
3
4
5
6
7
8
15
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
SO2Bn
Bz
20 (87)
21 (91)
22 (89)
2321 (89)
24 (78)
25 (88)
26 (86)
2721 (81)
28 (79)
29 (89)
30 (76)
3122 (89)
32 (80)
33 (75)
34 (76)
3521 (79)
36 (85)
37 (86)
38 (84)
39 (92)
1/4.3c
1/1.8
1/1.9
1/1.9
1/1.8c
1.5/1c
1.9/1
1.1/1c
1/7.3
1.2/1
1/1.2
1/2.4
1.2/1
4.0/1
4.0/1
1/1
Ac
Ac
Bnd
SO2Bn
Bz
Bnd
SO2Bn
Bz
16
17
18
19
16
17
18
19
Ac
Ac
Bnd
SO2Bn
Bz
1.1/1c
1/11.5
1/5.3c
1/4.0
1/2.4
1/4.0
1/3.9
1/3.2
1/1
Bnd
SO2Bn
Bz
9
9
10
11
12
13
14
15
16
17
18
19
20
10
11
12
13
14
15
16
17
18
19
20
Ac
Ac
Bnd
SO2Bn
Bz
Bnd
SO2Bn
Bz
Ac
Ac
Bnd
SO2Bn
Bz
Bnd
SO2Bn
Bz
1/1.1
1/1.4c
1/1
4.9/1
a
a
onlyc
Ac
Ac
onlyc
Bnd
2.8/1
Bnd
2.8/1
a
a
Determined by after isolation.
Determined by 1H NMR.
Determined by LC-Mass.
Determined by after isolation.
Determined by 1H NMR.
Determined by LC-Mass.
b
c
b
c
d
d
A standard donor for comparison.
A standard donor for comparison.
withdrawing effect competing with the
mote acyl group participation.
a-directing effect by re-
the 2.8/1 a/b ratio of the product from the glycosylation of the fully
benzyl-protected standard donor 4 with 19 (entry 20 in Table 2). It
is also noteworthy that in the glucosylations of all primary alcohol
2.3. Glucosylations with donors possessing an electron-
withdrawing group at O-4
acceptors 15, 16 and 17, the
b-directing effect by the electron-
withdrawing groups in the glucosyl donors increased with re-
spect to increasing electron-withdrawing ability (SO2Bn>Bz>Ac)
(entries 1e3, 5e7, and 9e11 in Table 2).
Because remote participation by the 4-O-acyl group in glucosyl
donors could also promote the b-selectivity in glucosylations, it is
difficult to distinguish between the electron-withdrawing and the
remote participation components of acyl protecting groups at O-4
on the glucosylation stereochemistry. Nevertheless, in the gluco-
sylations of secondary alcohol acceptors 18 and 19, the slightly
All electron-withdrawing protecting groups, SO2Bn, Bz, and Ac,
at the O-4 positions of glucosyl donors promote b-selective gluco-
sylation reactions. Thus, glucosylations of primary alcohol accep-
tors 15, 16, and 17 with glucosyl donors 5, 6, and 7 bearing an
electron-withdrawing group at the O-4 position provided gluco-
syl disaccharides 40 (EWG¼SO2Bn,
¼1/4.9), 42 (EWG¼Ac, ¼1/2.8), 43 (EWG¼SO2Bn,
44 (EWG¼Bz, ¼1/3.0), 46 (EWG¼SO2Bn, ¼1/11.5), 47
(EWG¼Bz, ¼1/5.3), and 48 (EWG¼Ac, ¼1/4.0), all favoring
the -anomers (entries 1e3, 5, 6, and 9e11 in Table 2). Even in
a
/b
¼1/5.7), 41 (EWG¼Bz,
a/
b
a
/b
a/b
¼1/2.0),
a
/b
a/b
higher
3.9 and 1/1.4, entries 14 and 18 in Table 2) compared with that by
the more electron-withdrawing benzylsulfonyl group of donor 5 (
b
-directing effect by the benzoyl group of donor 6 (
a
/b
¼1/
a
/b
a/b
b
a
/
glucosylations of the more sterically demanding secondary alcohol
acceptors 18, the electron-withdrawing groups in donors 5, 6, and 7
b
¼1/4.0 and 1/1.1, entries 13 and 17 in Table 2) may be attributed to
the additional b-directing effect from remote participation of the
exerted
(EWG¼SO2Bn,
(EWG¼Ac,
though the glucosylation of another secondary alcohol acceptor 19
with donors 5, 6, and 7 appeared to not quite be -selective, the
directing effect by the electron-withdrawing groups of 5, 6, and 7 in
these glucosylations was evident when the ratios of the prod-
ucts (
¼1/1.4e1/1, entries 17e19 in Table 2) were compared with
a
b
-directing effect, affording disaccharides 49
¼1/4.0), 50 (EWG¼Bz, ¼1/3.9), and 51
¼1/3.2), respectively (entries 13e15 in Table 2). Al-
benzoyl group at the O-4 position in the glucosyl donors.
a
/b
a/b
a/b
2.4. Galactosylations with donors possessing an electron-
withdrawing group at O-3
b
b-
a
/b
Only a very low
b-selectivity was observed in the galactosylation
a/b
of primary alcohol acceptor 15 with donor 8 bearing the strongly

5318
J.Y. Baek et al. / Tetrahedron 71 (2015) 5315e5320
Table 4
electron-withdrawing SO2Bn group at the O-3 position (
entry 1 in Table 3). In contrast, in the galactosylations of other ac-
a
/
b
¼1/1.6,
Galactosylations with donors 12e14 having an EWG at the O-4 position
ceptors, both primary alcohol acceptors 16 and 17 and secondary
alcohols acceptors 18 and 19 with donor 8, virtually no b-directing
effect was shown by the SO2Bn group at the O-3 position (entries 5,
9, 13, and 17 in Table 3). Unlike in glucosyl donors, there was no
clear indication for the existence of the b-directing effect by an
electron-withdrawing group (SO2Bn) at the O-3 position of the
galactosyl donors.
Entry
ROH
Donor
EWG
Product (yield, %)a
Ratiob
(a/b)
1
2
3
4
5
6
7
8
15
12
13
14
11
12
13
14
11
12
13
14
11
12
13
14
11
12
13
14
11
SO2Bn
Bz
75 (86)
76 (85)
77 (82)
58 (68)
78 (83)
79 (86)
80 (84)
62 (87)
81 (75)
82 (80)
83 (87)
66 (71)
84 (76)
85 (85)
86 (86)
70 (71)
87 (83)
88 (88)
89 (88)
74 (80)
1/1.5
5.3/1c
1.1/1
1.5/1
2.2/1
8.1/1
4.0/1c
2.1/1
1/1.3c
4.0/1c
1.5/1
1.1/1
4.0/1c
Table 3
Ac
Galactosylations with donors 8e10 having an EWG at the O-3 position
Bnd
SO2Bn
Bz
16
17
18
19
Ac
Bnd
SO2Bn
Bz
9
10
11
12
13
14
15
16
17
18
19
20
Ac
Entry
ROH
Donor
EWG
Product (yield, %)a
Ratiob
(a/b)
Bnd
SO2Bn
Bz
1
2
3
4
5
6
7
8
15
8
9
10
11
8
SO2Bn
Bz
55 (82)
56 (80)
57 (83)
58 (68)
59 (89)
60 (90)
61 (81)
62 (87)
63 (75)
64 (88)
65 (78)
66 (71)
67 (81)
68 (81)
69 (76)
70 (71)
71 (83)
72 (83)
73 (75)
74 (80)
1/1.6
1.2/1
1.1/1c
1.5/1
2.1/1
4.3/1
5.7/1
2.1/1
1.3/1
2.3/1
2.0/1
1.1/1
1.1/1c
8.1/1c
3.3/1
4.8/1
8.1/1c
24/1c
10.1/1
10.1/1
10.1/1c
3.2/1
Ac
Ac
Bnd
SO2Bn
Bz
Bnd
SO2Bn
Bz
1.1/1
a
onlyc
16
17
18
19
40/1c
40/1c
10.1/1
9
10
11
8
Ac
Ac
Bnd
SO2Bn
Bz
Bnd
9
a
Determined by after isolation.
Determined by 1H NMR.
Determined by LC-Mass.
10
11
12
13
14
15
16
17
18
19
20
9
b
c
10
11
8
Ac
Bnd
SO2Bn
Bz
d
A standard donor for comparison.
9
bearing an SO2Bn group at O-4 showed no
tries 5, 13, and 17 in Table 4).
However,
both primary and secondary alcohol acceptors with donors carry-
ing an acyl protecting group at O-4. In particular, the -directing
b-selectivity at all (en-
10
11
8
9
10
11
Ac
Bnd
SO2Bn
Bz
a-selectivity was observed in most galactosylations of
Ac
a
Bnd
effect by remote participation was more pronounced with the
benzoyl protecting group than with acetates. Thus, the gal-
a
Determined by after isolation.
Determined by 1H NMR.
Determined by LC-Mass.
b
c
actosylations with 4-O-benzoyl galactosyl donor 13 were highly
selective regardless of the acceptors, yielding disaccharides 76 (
¼5.3/1), 79 ( ¼8.1/1), 82 ( ¼4.0/1), 85 ( ¼10.1/1), and 88
a-
d
A standard donor for comparison.
a/
b
a
/b
a
/b
a/b
On the other hand,
a-selectivities were observed in gal-
(
a
/
b
¼40/1) (entries 2, 6, 10, 14, and 18 in Table 4). In contrast, the
a-
actosylations with certain donors carrying an acyl protecting group
at the O-3 position. Thus, galactosylations of both primary alcohol
acceptors 16 and 17 and secondary alcohol acceptors 18 and 19 with
galactosyl donor 9 bearing a benzoyl group at O-3 were all
lective, yielding galactosyl disaccharides 60 (
¼4.3/1), 64 (
¼2.3/1), 68 ( ¼8.1/1), and 72 ( ¼24/1), respectively (entries 6,
10, 14, and 18 in Table 3). The -directing effect by the acetyl group
at O-3 of the galactosyl donor was less pronounced compared with
the benzoyl group. Moreover, galactosylations of only certain ac-
ceptors, 16 and 17, with donor 10 bearing an acetyl group at O-3
directing effect by the acetyl group was observable only in the
galactosylations of certain acceptors such as 16 and 19, yielding
disaccharides 80 (
tries 7 and 19 in Table 4).
a
/
b
¼4.0/1) and 89 (
a/b
¼40/1), respectively (en-
a-se-
a
/b
a/
b
a
/b
a/b
2.6. Summary of directing effects by remote protecting
groups in glucosylations and galactosylations
a
Table 5 enumerates the expected and observed
a- and b-
directing effects by remote protecting groups at the O-3 and O-4
positions of donors in glucosylations and galactosylations. When
remote participation occurs during glycosylations, the expected
directing effect by acyl groups at O-3 of glucosyl donors and at O-3
were more a-selective (entries 7 and 11 in Table 3) than those with
standard tetrabenzyl galactosyl donor 11 (entries 8 and 12 in
Table 3).
and O-4 of galactosyl donors would be
a, whereas the directing
2.5. Galactosylations with donors possessing an electron-
withdrawing group at O-4
effect by acyl groups at O-4 of glucosyl donors would be
b
. Based on
our previous work on mannosylations, the expected effect by non-
participating electron-withdrawing groups, regardless of their po-
Once again, unlike the results from the glucosylations, the
b
-
sitions in donors, would be
Both and -directing effects by the remote electron-
b
-directing.19
selectivities in galactosylations with donors bearing electron-
withdrawing groups at O-4 were very low or unnoticeable. Gal-
actosylations of primary alcohol acceptors 15 and 17 with donor 12,
which has a strong electron-withdrawing SO2Bn group at O-4
a-
b
withdrawing groups at the O-3 position of glucosyl donors were
observed, as shown in Table 5. The glucosylations of primary al-
cohol acceptors with donors bearing a non-participating SO2Bn
yielded disaccharides 75 (
spectively, with a slight excess of
Table 4). Galactosylations of acceptors 16, 18, and 19 with donor 12
a
/
b
¼1/1.5) and 81 (
a
/
b
¼1/1.3), re-
group at O-3 were
ondary alcohol acceptors with donors possessing acyl groups at O-3
were -selective. Interestingly, however, both SO2Bn and acyl
b-selective, whereas the glucosylations of sec-
b
-anomers (entries 1 and 9 in
a

J.Y. Baek et al. / Tetrahedron 71 (2015) 5315e5320
5319
Table 5
Directing effects by remote electron-withdrawing groups in glucosylations and galactosylations
Donor
Positions (ax. or eq.)
Expected directing effect
Observed dominant directing effect (EWG on donors)
By non-participating EW effect
By remote participation
Glc
Glc
Gal
Gal
3-O-EWG (eq)
4-O-EWG (eq)
3-O-EWG (eq)
4-O-EWG (ax)
b
b
b
b
a
b
a
a
b
b
a
a
(SO2Bn) for 1ꢁOH acceptors (Acyl) for 2ꢁOH acceptors
a
(SO2Bn, Acyl)
(Acyl)
(Acyl)
groups at the O-4 position of glucosyl donors exhibited a
directing effect. Conversely, almost no -directing effect was ob-
served in galactosylations even with the strongly electron-
withdrawing SO2Bn group at either O-3 or O-4, whereas -direct-
ing effects by acyl groups at both the O-3 and O-4 positions of the
galactosyl donors were clearly seen. The magnitude of the
b
-
Table 6). Conversely, when glucosyl donor 4 and galactosyl donor
11, both bearing benzyl protecting groups, were activated with BSP
and Tf2O, the NMR spectra showed no sign of the generation of
triflate intermediates. These results also indicate that the electron-
b
a
withdrawing groups in the glucosyl donors make the
a-glycosyl
b
-
triflates more stable than the corresponding electron-withdrawing
groups in the galactosyl donors (entries 1 vs 7, 3 vs 8, and 4 vs 9 in
Table 6). These results, together with the results shown in Tables
1e4, indicate that the electron-withdrawing groups, which make
directing effect by the SO2Bn group in glucosylations appears to be
site-sensitive. Thus, the SO2Bn group at O-4 of glucosyl donors is
more
b
-directing than at O-3 of glucosyl donors in the glucosyla-
-directing effect of the
tions of various acceptors. In contrast, the
a
the
a
-glycosyl triflates more stable, also exhibit higher
b
-selectiv-
-gly-
-selective the
-glucosyl triflate
benzoyl group appears to be more pronounced than that of the
acetyl group, especially in galactosylations.
ities in glycosylations. In other words, the more stable the
cosyl triflate intermediates are, the more
glycosylations are. Specifically, high levels of
a
b
a
formation from all glucosyl donors possessing electron-
withdrawing groups (5e7; BnSO2, Bz, Ac) at O-4 corresponded
2.7. Detection of
relationship with the
a
-glycosyl triflate intermediates and their
b
-directing effect
well with the high to moderate
b-selectivities observed in the
glucosylations with 5e7.
We performed low temperature NMR experiments to detect a-
glycosyl triflate intermediates19,23 and determine their stabilities to
One of the crucial factors for
b-selectivity in the present study is
the generation of the -glycosyl triflate or the existence of a triflate
a
provide a better understanding of the role of remotely positioned
counteranion to the glycosyl oxocarbenium ion during glycosyla-
tion. To confirm the triflate counteranion effect of the glycosyl
oxocarbenium ion on the stereochemical outcome in the present
glycosylations, we performed glucosylations of primary alcohol
acceptor 15 with glucosyl bromide 90 as the donor by employing
either an AgClO4/SnCl2 or an AgOTf promoter. With AgClO4/SnCl2 as
the promoter, the glucosylation of 15 with 90, which bears a 4-O-
benzylsulfonyl group, in CH2Cl2 at ꢀ50 ꢁC afforded disaccharide 40
electron-withdrawing protecting groups on the b-directing effect.
Upon the activation of selected phenyl 1-thioglycosides 1, 2, 4e8,
11e13 with BSP and Tf2O in CD2Cl2 at ꢀ60 ꢁC, the NMR spectra
showed the generation of a-glycosyl triflates of variable intensities
and thermal stabilities from only the donors bearing the remote
electron-withdrawing protecting group (1, 2, 5e8, 12, 13; entries
1e5 and 7e9 in Table 6).
(
a
/
b
¼1/3.4), whereas the same glucosylation with AgOTf as the
promoter was highly -selective, yielding 40 (
¼1/7.0) with an
excess of -anomer (entries 1 and 2 in Table 7). For comparison, we
carried out the glucosylation of 15 with 2,3,4,6-tetra-O-benzyl-
Table 6
b
a/b
a
-Glycosyl triflates in low-temperature NMR experiments
b
a
-
glucopyranosyl bromide 91 possessing no electron-withdrawing
group by employing either AgClO4/SnCl2 or AgOTf as the pro-
moter. The
a
/
b
ratios of the two glucosylations,
a
/
b
¼1/3.1 and
a/
Entry
a
-triflates EWG on
Donor dH
1
dC
1
Relative Decomp.
b
¼1/2.9, were not markedly different (entries 3 and 4 in Table 7)
donor
ppm ppm intensity Temp, oC
and were nearly the same as those from the glucosylation of 15
with 90 employing AgClO4/SnCl2. This result confirms that the
triflate counteranion of the glucosyl oxocarbenium ion is indeed
of H1a
1
2
3
4
5
6
7
8
9
10
Glucosyl
a
3-O-BnSO2
-triflates 3-O-Bz
1
2
5
6
7
6.24 105.3 0.30
6.25 106.2 0.11
6.13 105.5 0.75
6.16 105.7 0.29
6.15 106.7 0.21
Not detected
ꢀ20 to ꢀ10
ꢀ20 to ꢀ10
ꢀ20 to ꢀ10
ꢀ30 to ꢀ20
ꢀ20 to ꢀ10
one of the crucial factors for b-selectivity in glucosylations with
donors bearing a remote electron-withdrawing group.
4-O-BnSO2
4-O-Bz
4-O-Ac
(Tetra-O-Bn)
4
Table 7
Galatosyl 3-O-BnSO2
a
8
12
13
6.22 106.8 0.09
6.20 106.8 0.24
6.25 106.3 0.08
Not detected
ꢀ30 to ꢀ20
ꢀ20 to ꢀ10
ꢀ30 to ꢀ20
Glycosylations of 15 with glucosyl bromide employing AgClO4/SnCl2 or AgOTf as
a promoter
-triflates 4-O-BnSO2
4-O-Bz
(Tetra-O-Bn) 11
a
The ratio of the H1 signal integration of the triflate to that of the corresponding
donor.
Entry
Donor
R1
Promoter
Product (yield, %)a
Ratiob
(a/b)
The results shown in Table 6 indicate that the a-glycosyl triflates
resulting from donors 1, 5, and 12, which possessed the stronger
electron-withdrawing benzylsulfonyl group at the O-3 or O-4 po-
sition, are more stable than the corresponding a-glycosyl triflates
resulting from donors 2, 6, and 13, which had the weaker electron-
withdrawing benzoyl groups (entries 1 vs 2, 3 vs 4, and 8 vs 9 in
1
2
3
4
90
90
91
91
SO2Bn
SO2Bn
Bn
AgClO4/SnCl2
AgOTf
AgClO4/SnCl2
AgOTf
40 (77)
40 (92)
23 (72)
23 (84)
1/3.4
1/7.0
1/3.1
1/2.9
Bn
a
Determined after isolation.
Determined by 1H NMR.
b

5320
J.Y. Baek et al. / Tetrahedron 71 (2015) 5315e5320
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observing only -directing effects by remote acyl groups of donors
in galactosylations. The non-participating SO2Bn group at the O-3
position of glucosyl donors exhibited -directing effects in gluco-
sylations of primary alcohol acceptors. At the O-4 position of glu-
cosyl donors, both SO2Bn and acyl groups are -directing in the
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a
b
b
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a
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a-directing effect by acyl groups is partly
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information for synthetic carbohydrate chemists to take advantage
of when selecting protecting groups for the synthesis of complex
carbohydrates.
Acknowledgements
This work was supported by a grant from the Korea National
Research Foundation of Korea through the Center for Bioactive
Molecular Hybrids (CBMH). Authors also acknowledge the support
by the BK 21 program from the Ministry of Education and Human
Resources Development of Korea.
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Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.06.014.
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