Introduction of 4-Chlorophenyl: A Protecting Group for the Hydroxy Function

Article abstract of DOI:10.1055/s-0036-1591984

4-Chlorophenyl ether was utilized as a new protecting group for the hydroxy function. This group was readily introduced to a sugar hydroxy group by using diaryliodonium triflate. Regioselective introduction of this protecting group at the vicinal cis -diol was achieved by using a copper catalyst and diaryliodonium triflate. This protecting group is stable under the Lewis acidic conditions of glycosylation, but it can be readily removed by the initial conversion into the corresponding 4-methoxyphenyl ether with use of a Pd catalyst, followed by oxidation with ammonium cerium (IV) nitrate [(NH ₄) ₂ Ce(NO ₃) ₆ ] (CAN).

Full text of DOI:10.1055/s-0036-1591984

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–G
letter
A
en
Y. Otsuka et al.
Letter
Synlett
Introduction of 4-Chlorophenyl: A Protecting Group for the
Hydroxy Function
Yuji Otsukaa,b
Toshihiro Yamamotoa,b
Koichi Fukase*b
6 examples
74–100%
O
O
O
base
HO
a Peptide Institute, Inc., Ibaraki, Osaka 567-0085, Japan
b Graduate School of Science, Osaka University, Toyonaka,
Osaka 560-0043, Japan
O
mono-ol
O
Pd cat.
MeOH
OTf
Ar
koichi@chem.sci.osaka-u.ac.jp
I
Cl
Cl
Cl
OMe
OH
O
OH
Cu cat.
base
O
HO
O
5 examples
65–86%
cis-diol
Received: 04.02.2018
Accepted after revision: 15.03.2018
Published online: 13.04.2018
to hydroxy groups on sugars. However, the direct introduc-
tion of an MP group to a hydroxy group by this method was
not successful. Therefore, in this paper, we describe the use
of 4-chlorophenyl ether (4-ClPhe) as a protecting group for
hydroxy functions. The 4-ClPhe can be readily introduced
to hydroxy functions by using diaryliodonium salts, and
this protecting group can then be removed by CAN through
conversion of 4-ClPhe into MP by using a Pd catalyst. The
regioselective introduction of 4-ClPhe ether into sugar vici-
nal cis-diols was also possible by utilizing diaryliodonium
salts and a copper catalyst developed by Onomura et al.5
We first attempted the direct introduction of the MP
ether into 1,2;3,4-di-O-isopropylidene-α-D-galactopyra-
nose (2) by using bis(4-methoxyphenyl)iodonium triflate
(1), which had been prepared from 4-methoxyiodobenzene
and anisole,6 in the presence of tBuOK as a base (Table 1).4
However, the yield of the desired product 3 was unsatisfac-
tory and byproducts were formed by aromatic ring modifi-
cations owing to the electron-rich aromatic system pos-
sessing a methoxy group (Table 1, entry 1). To avoid these
side reactions, we attempted to introduce a 4-ClPhe group
instead of an MP ether. In fact, in 2013, Buchwald et al. pro-
posed a useful method for performing the methoxylation of
DOI: 10.1055/s-0036-1591984; Art ID: st-2018-u0076-l
Abstract 4-Chlorophenyl ether was utilized as a new protecting group
for the hydroxy function. This group was readily introduced to a sugar
hydroxy group by using diaryliodonium triflate. Regioselective introduc-
tion of this protecting group at the vicinal cis-diol was achieved by using
a copper catalyst and diaryliodonium triflate. This protecting group is
stable under the Lewis acidic conditions of glycosylation, but it can be
readily removed by the initial conversion into the corresponding 4-me-
thoxyphenyl ether with use of a Pd catalyst, followed by oxidation with
ammonium cerium (IV) nitrate [(NH4)2Ce(NO3)6] (CAN).
Key words 4-chlorophenyl ether, 4-methoxyphenyl ether, carbo-
hydrate, protecting group, hydroxy function, regioselective arylation
The selective protection and removal of particular hydroxy
groups play a crucial role in the multistep syntheses of
complex carbohydrates and other polyhydroxylated com-
pounds.1 4-Methoxyphenyl (MP) ether has been used for
protecting the anomeric hydroxy function of carbo-
hydrates, but it has not yet been applied to protect other
hydroxy groups because efficient introduction methods are
lacking.2 The MP ether is stable under various reaction con-
ditions, including Lewis acid-catalyzed glycosylation, and it
can be readily cleaved through oxidation by ammonium
cerium (IV) nitrate [(NH4)2Ce(NO3)6]. Conversely, the MP
ether is inert to oxidation with 2,3-dichloro-5,6-dicyano-p-
benzoquinone (DDQ), whereas a 4-methoxyphenylmethyl
(MPM) ether is readily cleaved by both DDQ and CAN oxida-
tion.3 Recently, Olofsson et al. reported O-arylation of
hydroxy functions using electrophilic diaryliodonium salts
in the presence of a base.4 Various phenyl groups, such as 4-
nitrophenyl, 3-trifluoromethylphenyl, 3-azidopheyl, 4-azido-
phenyl, phenyl, and 4-tBu-phenyl groups, were introduced
aryl chlorides by using
a
Pd precatalyst system
(tBuBrettPhos Pd G3).7 Jensen et al. also reported the me-
thoxylation of 4-chlorobenzyl ether using the same precat-
alyst system.8 We expected that the 4-ClPhe ether can be
readily removed through a two-step procedure consisting
of the conversion of the 4-ClPhe ether to an MP ether, fol-
lowed by CAN oxidation. So far, the 4-ClPhe group has been
rarely used as a protecting group for hydroxy functions be-
cause of the rather harsh conditions required for the re-
moval of 4-ClPhe: Birch reduction followed by acid hydroly-
sis.9 We then elucidated 4-chlorophenylation by using the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

B
Y. Otsuka et al.
Letter
Synlett
symmetric diaryliodonium triflates 6 and the asymmetric
diaryliodonium triflates 5 and 7. As expected, 4-chloro-
phenylation proceeded smoothly with bis(4-chlorophenyl)-
iodonium triflate (6) to give the desired 4 in good yield
(81%) (Table 1, entry 3). The reaction with 4-chloro-
phenyl(4-methoxyphenyl)iodonium triflate (7) afforded 4
in the 83% yield, which is the highest among the reactions
evaluated (Table 1, entry 4).
Cl
OMe
tBuBrettPhos Pd G3 (0.1 equiv)
tBuBrettPhos (0.1 equiv)
tBuONa (4 equiv), MeOH (50 equiv)
O
O
O
O
CAN
O
O
O
O
2
O
O
1,4-dioxane
reflux, 0.5 h
84%
MeCN/H2O
9:1
rt, 15 min
88%
O
O
4
3
Methoxylation of the 4-ClPhe ether was then carried
out by employing the conditions developed by Buchwald et
al.7 Upon treatment of 4 with tBuBrettPhos Pd G3 (0.1
equiv), tBuBrettPhos (0.1 equiv), tBuONa (4 equiv), and
MeOH (50 equiv) in 1,4-dioxane under reflux, the methox-
ylated product 3 was obtained in good yield (Scheme 1).
The MP ether of the galactopyranose 3 was easily removed
by using CAN in MeCN/H2O to give 2 in 88% yield. Notably,
the 4-ClPhe ether was stable under various conditions (see
Supporting Information).
The introduction and removal of a 4-ClPhe ether were
then investigated with the secondary alcohols of glucopyra-
noside 8, fucopyranoside 9, and mannopyranoside 10 (Ta-
ble 2). 4-Chlorophenylation using 7 proceeded smoothly to
give the corresponding 4-ClPhe ethers in good yields.
Methoxylation of the 4-ClPhe ethers thus obtained also af-
forded good results. In the presence of the TIPS group and
the Piv group, methoxylation was carried out under milder
conditions by using Cs2CO3 as a base (entries 4 and 5).
Cleavage of the resulting MP ethers also proceeded smooth-
ly by using CAN. Although, during MP removal, the ben-
zylidene group of mannopyranoside 20 and the TIPS group
of glucopyranoside 21 were partially cleaved at room tem-
perature as a result of the acidic nature of CAN, the yields of
these removal reactions were improved when they were
conducted at 0 °C for five minutes.
Scheme 1 Methoxylation and removal of MP ether
As described above, the 4-ClPhe group was proven to be
a useful protecting group for the hydroxy function. Next,
we attempted the regioselective introduction of the 4-ClPhe
ether into vicinal cis-diols. Recently, Taylor et al. achieved
the regioselective O-arylation of the sugar triols using
Cu(OAc)2 and an arylboronic acid.10 Niu et al. also reported
the regioselective O-arylation using Cu(OTf)2, diaryliodoni-
um triflate, and a chiral ligand.11 However, the regioselec-
tive introduction of an aryl ether into vicinal diols, in the
absence of chiral ligands, has not been reported yet. Benzyl
α-D-mannopyranoside 23 was chosen as a diol substrate for
the investigation of a selective O-arylation performed by
using Onomura’s method.5 First, the role of copper reagents
in phenylation conducted with use of diphenyliodonium
triflate in the presence of Na3PO4 in toluene under reflux
was investigated (Table 3).
Although the reaction progressed even in the absence of
copper, the yield of the phenylated product was 24% in this
case, and the selectivity was low (2-OH/3-OH 1:1.5) (entry
1). Conversely, although the use of Cu(OTf)2 previously gave
a simple diol in high yield, the yield and selectivity of our
reaction (entry 2) were low. Subsequently, other copper re-
agents, i.e., CuI, CuCl2, CuCl, and CuBr, were tested, but the
Table 1 Introduction of MP Ether and 4-Chlorophenyl Ether
R
OTf
OTf
OTf
OTf
OH
O
I
I
ArAr'I OTf (4 equiv)
tBuOK (4 equiv)
O
O
MeO
OMe
O
Cl
Cl
Cl
O
O
toluene
rt, overnight
1
6
O
O
O
O
I
O
I
2
Cl
R = OMe 3
= Cl .4
OMe
5
7
Entry
Diaryliodonium triflate
Product
Isolated Yield (%)
1
2
3
4
1
5
6
7
3
4
4
4
68a
64
81
83
a Yield includes byproducts modified on the aromatic ring.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

C
Y. Otsuka et al.
Letter
Synlett
yield and the selectivity of the reaction did not improve
(entries 3–6). On the other hand, when CuBr2 was used, the
desired product was obtained in 68% yield with good regi-
oselectivity (2-OH/3-OH 1:7.9) (entry 7). Among the bases
tested, Na3PO4 was the best, both in terms of yield and regi-
oselectivity, as shown in Table 3. The use of diaryliodonium
triflate 6 and tBuOK at room temperature resulted in low
yield and selectivity (entry 13). Diphenylated compound 25
was obtained by using Cs2CO3 as a base in 32% yield.
As discussed above, the combination of CuBr2 and Na3PO4
was found to be superior for the regioselective phenylation
of cis-diols. We then examined the 4-methoxyphenylation
and 4-chlorophenylation of mannopyranoside 23 by using
the iodonium triflates 1, 5, 6, and 7 under similar condi-
tions. The reaction of 23 with bis(4-methoxyphenyl)iodoni-
um triflate (1) afforded the MP mannose derivatives 26a
and 26b in 10% total yield. Furthermore, large amounts of
the by-products were obtained (Table 4, entry 1). The reac-
tion of 23 with the asymmetric 4-chlorophenyl(phenyl)io-
donium triflate (5) resulted in the formation of a mixture of
the desired 4-ClPhe ethers 27a and 27b along with the un-
desired phenylated products 24a and 24b (entry 2). A mix-
ture of the desired 4-ClPhe ethers 27a and 27b alongside
the MP derivatives 26a and 26b was obtained by using
the asymmetric 4-chlorophenyl(4-methoxyphenyl)iodonium
triflate (7) (entry 3). Notably, use of symmetric and highly
reactive bis(4-chlorophenyl)iodonium triflate (6) resulted
in the formation of the desired products 27a and 27b in
good yield (75%) with moderate regioselectivity (27a/27b
1:5) (entry 4).
The regioselective 4-chlorophenylation using bis(4-
chlorophenyl)iodonium triflate (6) was then attempted on
other vicinal cis-diols (Table 5). The regioselectivity of the
reaction using ribofuranoside 28 was poor (entry 1). Con-
versely, the 4-chlorophenylation of other 6-membered sug-
ars, in particular rhamnopyranoside 29, galactopyranoside
30, and fucopyranoside 31, proceeded with a reasonable
degree of regioselectivity (entries 2–4). Under the present
reaction conditions, the equatorial hydroxy group in C-3
position was more reactive than the adjacent axial hydroxy
groups. However, these reaction conditions cannot be ap-
plied for the protection of sugars possessing an acyl pro-
tecting group. In fact, 4-chlorophenylation of 2,6-di-O-
benzoyl-(4-methoxyphenyl)-β-D-galactopyranoside gave a
complex mixture containing de-benzoylated compounds
(data not shown). The reaction conditions were not appli-
Table 2 4-Chlorophenylation, Methoxylation, and Deprotection for Several Sugars
tBuBrettPhos Pd G3 (0.1 equiv)
tBuBrettPhos (0.1 equiv)
MeO
Cl
tBuOK (4 equiv)
CAN
O
O
tBuONa (4 equiv), MeOH (50 equiv)
7 (4 equiv)
HO
+
HO
O
O
toluene
rt, overnight
MeCN/H2O = 9/1
rt, 15 min
O
1,4-dioxane
reflux, 0.5 h
O
sugar 8–12
13–17
18–22
8–12
Entry
Sugar
4-Chlorophenylation, isolated
yield (%)
Methoxylation, isolated
yield (%)
Removal of MP, isolated
yield (%)
BnO
O
BnO
O
BnO
1
2
13 (90)
18 (86)
19 (90)
8 (93)
OH
8
OMe
O
OBn
14 (quant.)
9 (quant.)
OBn
OH
9
OH
Ph
O
O
O
3
15 (91)
20 (93)
10 (93)a
BnO
OBn
SPh
10
TIPSO
HO
O
21 (76)b
22 (72)b
11 (85)a
12 (76)
BnO
4
5
16 (74)
17 (85)
OBn
11
PivO
HO
BnO
O
SPh
OBn
12
a Reaction was performed at 0 °C, 5 min.
b Cs2CO3 was used instead of tBuONa.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

D
Y. Otsuka et al.
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Synlett
Table 3 Regioselective Phenylation of a Mannose Derivative
Cu (0.3 equiv)
Ph2IOTf (2 equiv)
base
OH
O
OPh
O
OH
O
OPh
O
Ph
O
Ph
O
Ph
O
Ph
O
O
O
O
O
HO
+
+
HO
PhO
PhO
toluene
reflux, 3 h
OBn
OBn
OBn
OBn
23
24a
24b
25
Entry
Reagent
Base (equiv)
Isolated yield of 24 (%)
24a/24ba
Yield of 25 (%)
1
2
–
Na3PO4 (4)
Na3PO4 (4)
Na3PO4 (4)
Na3PO4 (4)
Na3PO4 (4)
Na3PO4 (4)
Na3PO4 (4)
NaF (4)
24
17
21
8
1:1.5
1:1.4
1:1.8
1:1.9
1:1.5
1:1.7
1:7.9
–
trace
trace
trace
trace
trace
trace
0
Cu(OTf)2
CuI
3
4
CuCl2
CuCl
CuBr
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
–
5
20
32
68
0
6
7
8
0
9
Cs2CO3 (4)
tBuOK (4)
K2CO3 (4)
DIEA (4)
36
20
60
48
24
1:2.2
1:1.0
1:4.2
1:2.2
1:1.6
32
10
11
12
13b
15
trace
0
tBuOK (4)
0
a Ratios determined by 1H NMR spectroscopy.
b Reaction was performed at rt.
Table 4 4-Methoxylphenylation and 4-Chlorophenylation of Manno-
pyranoside 23
cable to the protection of mono-ols. The reaction of 6-OH
free galactopyranose derivative 2 with CuBr2-diaryliodoni-
um triflate system gave 4 in low yield (5%).
OH
O
CuBr2 (0.3 equiv)
Na3PO4 (4.0 equiv)
diaryliodonium triflate (2.0 equiv)
R
Finally, the selective removal of the 4-ClPhe ether and 4-
nitrophenyl (4-NP) ether was investigated (Scheme 2). The
4-NP ether was easily introduced into mannopyranoside
27b by using 4-nitrophenylphenyliodonium triflate (36) to
obtain compound 37 in good yield. We then investigated
the selective removal of the 4-ClPhe or 4-NP groups from
37. The methoxylation of 37 was not achieved by using
tBuOK as a base because a by-product was obtained. There-
fore, methoxylation was carried out with Cs2CO3 as a base
to give MP ether 38 in good yield. Subsequently, the MP
ether in 38 was removed selectively by using CAN in the
presence of the incorporated 4-NP ether. Compound 38 was
converted to an acetamidophenyl ether 40 by reduction
of the nitro moiety with zinc followed by acetylation.12 The
4-acetamidophenyl ether was selectively removed with use
of CAN in the presence of the incorporated 4-ClPhe ether.
Thus, 4-ClPhe ether and 4-NP ether can be orthogonally
used for their selective removal as aryl ether protecting
groups.
Ph
O
O
O
23
O
toluene
reflux, 3 h
OBn
Ph
O
O
O
R
HO
OBn
24a,b
R = H
26a,b
27a,b
= OMe
= Cl
Entry
Diaryliodonium
triflate
Products
Ratio
(isolated yield, %)a
1
2
1
5
26a,b (10)
26a/26b 1:1.4
27a,b (10)
24a,b (17)
27a/27b 1:2.0
24a/24b 1:1.7
3
4
7
6
27a,b (24)
26a,b (33)
27a/27b 1:1.7
26a/26b 1:3.0
27a,b (75)
27a/27b 1:5.0
a Ratios determined by 1H NMR spectroscopy.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

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NO2
OTf
O
tBuOK (1.5 equiv)
CAN
I
+
27b
Ph
O
O
no reaction
O
O
toluene
rt, 1 h
87%
MeCN/H2O
0 °C, 5 min
O2N
OBn
36 (1.5 equiv)
37
NO2
Cl
NO2
tBuBrettPhos Pd G3 (0.1 equiv)
tBuBrettPhos (0.1 equiv)
Cs2CO3 (15 equiv)
O
Ph
O
O
O
O
MeOH (50 equiv)
CAN
O
37
Ph
O
O
dioxane
reflux, 0.5 h
77%
MeCN/H2O
0 °C, 5 min
99%
O
HO
OBn
OBn
MeO
38
39
NHAc
1) Zn, AcOH
rt, 1 h
O
CAN
Ph
O
O
37
27b
O
2) Ac2O, pyridine
rt, 15 min
quant. (for 2 steps)
MeCN/H2O
0 °C, 5 min
92%
O
OBn
Cl
40
Scheme 2 Orthogonal removal of two aryl protecting groups, 4-chlorophenyl ether and 4-nitrophenyl ether
Table 5 4-Chlorophenylation of Several Sugar Derivatives
HO
O
CuBr2 (0.3 equiv)
O
Na3PO4 (4 equiv)
HO
O
+
6
toluene
HO
reflux, 3 h
28–31
32–35
Cl
Entry
1
Sugar
Products
Isolated yield (%)
Ratio
TBDPSO
OMe
TBDPSO
OMe
O
O
32a/32b
1:1.2
R2O OR1
65
HO OH
R1 = 4-ClPhe, R2 = H 32a
R1 = H, R2 = 4-ClPhe 32b
28
OBn
O
OBn
O
BnO
BnO
33a/33b
1:1.7
R2O
OR1
2
3
HO
86
86
OH
R1 = 4-ClPhe, R2 = H 33a
R1 = H, R2 = 4-ClPhe 33b
29
OBn
OBn
R2O
HO
O
O
HO
OMP
R1O
OMP
34a/34b
2.4:1
BnO
BnO
R1 = 4-ClPhe, R2 = H 34a
R1 = H, R2 = 4-ClPhe 34b
30
OMe
OMe
O
O
OBn
OBn
OR1
R2O
35a/35b
3.3:1
OH
OH
4
80
31
R1 = 4-ClPhe, R2 = H 35a
R1 = H, R2 = 4-ClPhe 35b
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

F
Y. Otsuka et al.
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Synlett
In summary, we have shown that the protecting group
4-chlorophenyl ether, which has not been used for the pro-
tection hydroxy groups so far, can be easily introduced into
sugar hydroxyl groups by using diaryliodonium triflate.13
This protecting group can then be removed by conversion
into an MP ether by initial methoxylation with use of a Pd
catalyst followed by oxidation with CAN.14 We have also
shown that 4-chlorophenyl ether can be regioselectively in-
troduced to some vicinal cis-diols in pyranose sugars by us-
ing a copper catalyst and diaryliodonium triflate.15 The 4-
chlorophenyl ether and 4-nitrophenyl ether are orthogo-
nally removable protecting groups. Currently, we are devel-
oping applications to carbohydrate synthesis of the chemis-
try described herein using aryl ether protecting groups.
(12) Fukase, K.; Yasukochi, T.; Nakai, Y.; Kusumoto, S. Tetrahedron
Lett. 1996, 37, 3343.
(13) General Procedure for 4-Chlorophenylation of Mono-ols
Sugar mono-ol (100 mg, 0.384 mmol, 1.0 equiv) was stirred in
toluene (3.8 mL, 0.1 M). To the solution were added 4-chloro-
phenyl(4-methoxyphenyl)iodonium trifluoromethanesulfon-
ate (7, 760 mg, 1.54 mmol, 4.0 equiv) and tBuOK (172 mg, 1.54
mmol, 4.0 equiv), and the mixture was stirred for overnight at
rt. Upon completion, the mixture was concentrated in vacuo.
The resulting crude product was purified by flash column chro-
matography on silica gel (Toluene/AcOEt = 5/1) to afford the
corresponding 4-ChPhe protected sugar.
(14) 1,2:3,4-Di-O-isopropylidene-6-O-(4-chlorophenyl)-α-D-
galactopyranose (4)
117.5 mg (83%), as a colorless oil.
1H NMR (CDCl3, 400 MHz): δ = 7.22–7.20 (m, 2 H, Cl-Ph-OR-2H,
Cl-Ph-OR-6H), 6.88–6.86 (m, 2 H, Cl-Ph-OR-3H, Cl-Ph-OR-5H),
5.56 (d, J = 5.03 Hz, 1 H, H-1), 4.65 (dd, J = 8.01, 2.52 Hz, 1 H, H-
3), 4.35–4.33 (m, 2 H, H-2, H-4), 4.16–4.08 (m, 3 H, H-5, H-6, H-
6'), 1.52 (s, 3 H, isopropyl), 1.47 (s, 3 H, isopropyl), 1.36 (s, 3 H,
isopropyl), 1.34 (s, 3 H, isopropyl); 13C NMR (CDCl3, 100 MHz):
δ = 157.2, 129.2, 125.8, 116.1, 109.5, 108.7, 96.3, 70.9, 70.6,
70.5, 67.0, 66.2, 26.0, 26.0, 24.9, 24.4; HRMS: m/z calcd for
Funding Information
This work was partially supported by JSPS KAKENHI Grant Number
15H05836 (KF) in Middle Molecular Strategy and JSPS KAKENHI
Grant Number 16H01885 (KF).
)(
C
18H23ClNaO6 [M + Na]+: 393.1075; found : 393.1061.
(15) General Procedure for Methoxylation of 4-Chlorophenyl
Protecting Groups
Acknowledgment
A mixture of 4-ChPhe-protected sugar (12 mg, 0.0324 mmol,
1.0 equiv), tBuBrettPhos Pd G3 (2.8 mg, 0.00324 mmol, 0.1
equiv), tBuBrettPhos (1.6 mg, 0.00324 mmol, 0.1 equiv), tBuONa
(12.5 mg, 0.139 mmol, 4.0 equiv) and MeOH (0.066 mL, 50
equiv) was stirred in dioxane (0.324 mL, 0.1 M) under Ar and
heated to reflux for 0.5 h. After diluting with AcOEt, the organic
phase was washed with H2O and brine, dried over Na2SO4, fil-
tered, and concentrated in vacuo. The resulting crude product
was purified by flash column chromatography on silica gel
(n-Hexane/AcOEt = 1/1) to afford the corresponding MP-pro-
tected sugar.
We are grateful to Dr. Kazuya Kabayama, Dr. Atsushi Shimoyama, and
Dr. Yoshiyuki Manabe of Osaka University, for their helpful discus-
sions.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591984.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
1,2:3,4-di-O-isopropylidene-6-O-(4-methoxyphenyl)-α-D-
galactopyranose (3)
References and Notes
10.0 mg (84%), as a colorless oil.
(1) Lawandi, J.; Rocheleau, S.; Moitessier, N. Tetrahedron 2016, 72,
6283.
(2) (a) Matsuzaki, Y.; Ito, Y.; Nakahara, Y.; Ogawa, T. Tetrahedron
Lett. 1993, 34, 1061. (b) Mori, M.; Ito, Y.; Ogawa, T. Carbohydr.
Res. 1989, 192, 131.
(3) (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett.
1982, 23, 885. (b) Mitra, A.; Mukhopadhyay, B. RSC Adv. 2016, 6,
85135. (c) Santra, A.; Misra, A. K. Tetrahedron: Asymmetry 2010,
21, 2612. (d) Budhadev, D.; Mukhopadhyay, B. Tetrahedron
2015, 71, 6155.
1H NMR (CDCl3, 400 MHz): δ = 6.90–6.86 (m, 2 H, MeO-Ph-OR-
2H, MeO-Ph-OR-6H), 6.83–6.79 (m, 2 H, MeO-Ph-OR-3H, MeO-
Ph-OR-5H), 5.57 (d, J = 5.03 Hz, 1 H, H-1), 4.64 (dd, J = 7.78, 2.29
Hz, H-3), 4.36–4.33 (m, 2 H, H-2, H-4), 4.16–4.07 (m, 3 H, H-5,
H-6), 3.76 (s, 3 H, MeO), 1.51 (s, 3 H, isopropyl), 1.47 (s, 3 H, iso-
propyl), 1.36 (s, 3 H, isopropyl), 1.34 (s, 3 H, isopropyl); 13C NMR
(CDCl3, 100 MHz): δ = 153.9, 152.7, 115.9, 114.5, 109.4, 108.7,
96.3, 71.0, 70.6, 67.3, 66.1, 55.7, 26.0, 26.0, 24.9, 24.4; HRMS:
m/z calcd for C19H26NaO7 [M + Na]+: 389.1571; found: 389.1565.
(16) General Procedure for Regioselective 4-Chlorophenylation of
cis-Diols
(4) Tolnai, G. L.; Nilsson, U. J.; Olofsson, B. Angew. Chem. Int. Ed.
2016, 55, 11226.
Under Ar, a test tube was charged with CuBr2 (3.7 mg, 0.0167
mmol, 0.3 equiv) and Na3PO4 (37 mg, 0.223 mmol, 4.0 equiv),
and then toluene (0.1 M) was added. The mixture was stirred
for 10 min at rt. Sugar cis-diol (20.0 mg, 0.0558 mmol, 1.0
equiv) and bis(4-chlorophenyl)iodonium trifluoromethanesul-
fonate (41.8 mg, 0.0837 mmol, 1.5 equiv) were added and the
reaction mixture was heated to reflux for 1 h. Then bis(4-chlo-
rophenyl)iodonium trifluoromethanesulfonate (16.3 mg,
0.0227 mmol, 0.5 equiv) was added and the reaction mixture
was heated to reflux for 2 h. The mixture was cooled to rt and
water and sat. aqueous NH4Cl were added. After diluting with
AcOEt, the organic phase was washed with H2O and brine, dried
(5) Kuriyama, M.; Hamaguchi, N.; Onomura, O. Chem. Eur. J. 2012,
18, 1591.
(6) Zhu, M.; Jalalian, N.; Olofsson, B. Synlett 2008, 592.
(7) Cheung, C. W.; Buchwald, S. L. Org. Lett. 2013, 15, 3998.
(8) Viuff, A. H.; Heuckendorff, M.; Jensen, H. H. Org. Lett. 2016, 18,
5773.
(9) Marshall, J. A.; Partridge, J. J. J. Am. Chem. Soc. 1968, 90, 1090.
(10) Dimakos, V.; Graham, E.; Garrett, G. E.; Taylor, M. S. J. Am. Chem.
Soc. 2017, 139, 15515.
(11) Shang, W.; Mou, Z-D.; Tang, H.; Zhang, X.; Liu, J.; Fu, Z.; Niu, D.
Angew. Chem. Int. Ed. 2018, 57, 314.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

G
Y. Otsuka et al.
Letter
Synlett
over Na2SO4, filtered, and concentrated in vacuo. The resulting
crude product was purified by flash column chromatography on
silica gel (Toluene/AcOEt = 10/1) to afford the corresponding 4-
ChPhe protected sugar.
Benzyl 4,6-O-benzylidene-3-O-(4-chlorophenyl)-α-D-mann-
opyranoside (27b)
4.64 (dd, J = 9.61, 3.66 Hz, 1 H, H-3), 4.54 (dd, J = 11.9 Hz, 1 H,
PhCH2), 4.30 (dd, J = 10.1, 4.58 Hz, 1 H, H-6), 4.25 (dd, J = 9.61,
9.61 Hz, 1 H, H-4), 4.23–4.21 (m, 1 H, H-2), 3.99 (ddd, J = 10.1,
9.61, 4.58 Hz, 1 H, H-5), 3.90 (dd, J = 10.1, 10.1 Hz, 1 H, H-6'),
2.60 (d, J = 2.29 Hz, 0.9 H, OH); 13C NMR (CDCl3, 100 MHz): δ =
156.6, 137.1, 136.6, 129.3, 128.9, 128.6, 128.2, 128.2, 127.2,
125.9, 118.6, 101.6, 99.2, 77.7, 76.6, 70.0, 69.6, 68.8, 63.9;
HRMS: m/z calcd for C26H25NaClO6 [M + Na]+: 491.1232; found:
491.1216.
27a, 27b (75%), as a colorless oil.
1H NMR (CDCl3, 400 MHz): δ = 7.39–7.29 (m, 10 H, Ph), 7.23–
7.19 (m, 2 H, ClPh), 7.03–6.99 (m, 2 H, Cl-Ph), 5.60 (s, 1 H,
PhCH), 5.01 (d, J = 1.37 Hz, H-1), 4.74 (d, J = 11.9 Hz, 1 H, PhCH2),
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G