Sub-stoichiometric reductive etherification of carbohydrate substrates and one-pot protecting group manipulation

Article abstract of DOI:10.1039/d0ob00252f

In this study, we report a new reductive etherification procedure for protection of carbohydrate substrates and its application for one-pot preparation of glycosyl building blocks. The reported procedure features the use of polymethylhydrosiloxane (PMHS)

Full text of DOI:10.1039/d0ob00252f

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DOI: 10.1039/D0OB00252F
Sub-Stoichiometric Reductive Etherification of Carbohydrate
Substrates and One-Pot Protecting Group Manipulation
Chiao Wen Chen, Ching Chi Wang, Xin Ru Li, Henryk Witek, and Kwok-Kong Tony Mong*a
Received 00th January 20xx,
Accepted 00th January 20xx
In this study, we report a new reductive etherification procedure for protection of carbohydrate substrates and its
application for one-pot preparation of glycosyl building blocks. The reported procedure features the use of
polymethylhydrosiloxane (PMHS) as a sub-stoichiometric reducing agent, which prevents the transilylation side reaction and
improves the efficiency of the reductive etherification method. Application of the PMHS reductive etherification procedure
for one-pot protecting manipulation are described.
DOI: 10.1039/x0xx00000x
(PMHS) is used as a sub-stoichiometric reagent, which prevents
the transilylation side reaction. In development of the
etherification method, we also clarified the experimental
conditions that enable the suppression of the transacetalation.
Introduction
Protecting group manipulations are mandatory in chemical
synthesis of oligosaccharides and related glycoconjugates, where
the polyhydroxyl glycosyl substrates are properly protected for
regio- and stereo-selective glycosylations.1-4 An elegant strategy
to streamline protecting group manipulation is one-pot
regioselective protection and/or deprotection; in which two or
more reaction steps are combined into a one-pot reaction
sequence.5-10 A key step in such one-pot protecting group
manipulation is the trialkylsilane reductive etherification. In the
70s, Doyle et al. reported the reductive etherification of carbonyl
compounds in alcohols using triethylsilane (Et3SiH) as the
reducing source;11 thereafter, various related reductive
etherification procedures have evolved.12
O
O
HO
Ph
O
Silylation and Et3SiH-
reductive etherification
procedure
O
O
NapO
Ph
STol
O
STol
NHTroc
NHTroc
N-Troc protected
thioglucosamine 1
2 (65%)
Ref 14
O
O
TESO
+
Ph
O
Naph
O
O
NapO
O
STol
STol
NHTroc
+
NHTroc
3 (21%)
triethylsilyl product 4 (~7%)
Scheme 1. Transacetalation and transilylation side reactions in Et3SiH reductive
etherification of thioglucosamine 1 at 0 °C.
In a project concerning the preparation of thioglucosamine
building block for synthesis of glucosamine glycans, the C-3
hydroxyl of N-trichloroethoxycarbonyl (Troc)-thioglucosamine Results and discussion
113 was protected with a naphthylmethyl (Nap) protecting group
1.1 Development of the PMHS Reductive Etherification
via a Et3SiH reductive etherification procedure.14 Thus, 1 was
silylated with hexamethyldisilazane (HMDS) to give a TMS
protected intermediate, which was subjected the etherification at
0 °C. However, the reaction afforded a mixture of desired
alkylation product 2, transacetalation product 3, and
transilylation product 4 in 65%, 21%, and 7%, respectively
(Scheme 1). Products 2 and 3 were not separable by the column
chromatography.15 The formation of transacetalation product 3
implicates the vulnerability of the benzylidene acetal. The
formation of transilylation product 4 should stem from the use of
Et3SiH.12d
To improve the applicability of the reductive etherification
procedure, we sought to search for solutions to address the
aforementioned issues. Herein, we report a new reductive
etherification procedure for protection of carbohydrate
substrates. In the new procedure, polymethylhydrosiloxane
At first, we sought to elucidate the influence of temperature on
transacetalation and transilylation under the Et3SiH reductive
etherification conditions (Table 1). Thus, substrate 1 was first
converted to 3-O-TMS-protected thioglucosamine 1a via the
HMDS silylation. Upon completion of the silylation, the reaction
was worked up to give crude TMS-protected thioglucosamine 1a,
which was used for etherification.16 Thus, 1a was treated with 2-
naphthylaldehyde (NapCHO), Et3SiH, and 0.1 equiv. of
trimethylsilyl trifluoromethanesulfonate (TMSOTf) at 30 °C
and 78 °C in accordance with literature procedures (Table 1,
entries 1 and 2).12e,14 In comparison with the reductive
etherification in Scheme 1, the formation of transacetalation
product 3 was greatly reduced at these sub-zero temperatures,
though the formation of transilylation product 4 was enhanced.
Further decreasing the reaction temperature to 86 °C
impractical for TMS-protected thioglucosamine 1a due to it poor
solubility.6,17,18 Increasing the amount of TMSOTf to 0.2 equiv.
did improve the yield of the etherification, but some
transilylation product 4 (~5%) still remained (entry 3).
a. Applied Chemistry Department, National Chiao Tung University, 1001, University
Road, Hsinchu City, Taiwan
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: general PMHS reductive
etherification and one-pot protecting group manipulation procedure, NMR
spectroscopic data of 24, 79, 10a10k, 12a12k, 17, 18, 21, and 24 are available.
See DOI: 10.1039/x0xx00000x
In the literature, PMHS has been used as a hydride source for
various reduction reactions,19-21 although its applicability to
glycosyl substrates has rarely been studied.22 Hence, we were of
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ARTICLE
Journal Name
interest to explore the utility of PMHS in the reductive stoichiometric amount of PMHS afforded an excellent yield
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etherification
of
carbohydrate
substrates.
Initially, (83%) of 2. Further reduction of PMHS tDoO0I:.2105.1e0q3u9/iDv0. OreBn0d0e2r5e2dF
thioglucosamine 1a was treated with 1.1 equiv. of NapCHO, 1.0 a slower reaction and although the reaction rate could be
equiv. of PMHS (number average molecular weight, Mn = 1900), improved by addition of 0.4 equiv. of TMSOTf or by raising the
and 0.2 equiv. of TMSOTf at 78 °C (Entry 4). To our reaction temperature to 30 °C. Both of the modified procedures
satisfaction, the reaction was complete in 2 h affording desired enhanced formation of the transacetalation product 3 (Entries 7
alkylation product 2 in 82% yield with no transilylation product. and 8). Nevertheless, when benzaldehyde (PhCHO) was used as
For comparison, the reductive etherification of 1a was repeated the etherification reagent, a higher reaction temperature and a
with dimethylphenyl silane (Me2PhSiH) (Entry 5), however this lower dosage of PMHS were acceptable because both of the
silane reagent was less reactive than either PMHS or Et3SiH, and transacetalation and reductive etherification would give the same
alkylation product 2 was obtained in only a moderate yield (40%), alkylation product 6 (Entry 9). However, further reduction of
together with unreacted 1a and transilylation product 5.
PMHS to 0.15 equiv. was ineffective even a 0 °C reaction
As PMHS contains multiple hydride-donating (SiH) groups, temperature was applied (Entry10). Based on the
it is logical to reduce the stoichiometric amount of the reagent. aforementioned studies, the reaction conditions for entries 6 and
Accordingly, the etherification of 1a was performed with 0.5 9 were chosen for implementation of the PMHS reductive
equiv. of PMHS at 60 °C (Entry 6). Satisfyingly, this sub- etherification procedure.
Table 1: Sequential Silylation and Reductive Etherification Procedure
O
O
RO
Ph
NapCHO or PhCHO (1.1 equiv)
TMSOTf (equiv)
O
STol
HMDS (1.2 equiv)
TMSOTf (0.4
equiv) DCM, RT
Silane A, B or C (equiv)
DCM, MS (10 wt% wrt DCM), T oC
O
O
HO
NHTroc
Ph
workup with
NH4Cl(aq)
O
O
O
TMSO
Ph
O
STol
2 R = Nap; 6 R = Bn
STol
NHTroc
+
NHTroc
O
O
NapO
Naph
Thioglucosamine 1
O
NHTroc
3-O-TMS protected
thioglucosamine 1a
STo
l
3
+
Silane :
O
O
n
O
O
Ph
O
Me
Me
Et
Et
Me3Si
Si
SiMe3
Me2PhSiH C =
Si
Si
STol
NHTroc
4 R' = TES; 5 R' = Me2PhSi
R'O
Me
H
Et3SiH A =
PMHS B =
Ph
H
H
Et
Entry
Aldehyde
(equiv.)
Silane reducing
agent (equiv.)
A (1.2)
TMSOTf
(equiv.)






4
T (oC)
Time
(h)
2
2
2
2
4
2
4
2
2
2
Desired product
2 or 6 (%)a
2 (56)
2 : 3 ratio
Transilylation
product (%)
Remark
from NMR
96 : 4
97 : 3
97 : 3
97 : 3
98 : 2
97 : 3
92 : 8
77 : 23
-
1
2
3
4
5
6
7
8
9
NapCHO (1.1)
NapCHO (1.1)
NapCHO (1.1)
NapCHO (1.1)
NapCHO (1.1)
NapCHO (1.1)
NapCHO (1.1)
NapCHO (1.1)
PhCHO (1.1)
PhCHO (1.1)
4, 21
4, 18
4, 5
-
Ref 12e
Ref 14,17
30
78
78
78
60
60
60
30
30
0
A (1.2)
A (1.2)
B (1.0)
C (1.2)
2 (61)
2 (80)
2 (82)
2 (40)
2 (83)
2 (81)
2 (65)
6 (83)
-
-
5, 20
incomplete
B (0.5)
-
-
-
-
-
-
-
-
-
-
B (0.25)
B (0.25)
B (0.25)
B (0.15)


0.2
10
6 (65)
-
a Yields of 2 from entries 1-8 were derived from the ratio of 2 and 3 in proton NMR spectrum.
To gain insight to the mechanistic aspect of the transacetalation would prevail. For validation, we repeated the
transacetalation reaction, 4,6-O-benzylidene protected N-Troc transacetalation experiment with p-nitrobenzaldehyde
thioglucosamine 6 was treated 0.1 equiv. of TMSOTf in the (pNO2PhCHO) (Scheme 2c). After 18 h, ~ 90% of the
absence or presence of NapCHO (Schemes 2a and 2b). In the benzylidene group of 6 was replaced with pNO2PhCHO to give
absence of NapCHO, ca. 50% of thioglucosamine 6 underwent transacetalation product 9, which presumably acquired a more
debenzylidenation to give thioglucosamine diol 7 (Scheme 2a). stable acetal group. Notably, product 9 existed as a pair
Of note, the anomeric configuration of thioglucosamine 6 and diastereomers, which were characterized by a pair arylidene
diol 7 was stable throughout the course of the reaction. proton signals at 5.62 and 6.14 ppm in ~ 5.7:1 R:S ratio
Interestingly, in the presence of NapCHO, a 3:2 inseparable (assignment supported by 1D and 2D NMR spectra, see SI).
mixture of transacetalation product 8 and thioglucosamine Similar to the reactions in schemes 2a and 2b, no sign of
substrate 6 was obtained (Scheme 2b).
anomerization was observed.
Based on the reactions in Schemes 2a and 2b, the 1.2 Scope and Limitations of the PMHS Reductive Etherification
transacetalation is likely attributed to
a
consecutive
With the PMHS reductive etherification procedure in hands, we
explored its substrate scope and limitations. To this end, a series
of polyol substrates (10ac) and glycoside substrates (10dk)
debenzylidenation and acetal formation process. Thus, we
hypothesized that if the arylidene group of the transacetalation
product is more stable than that of the starting substrate, then the
2 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
(a)
Ph
either NapCHO or PhCHO to give desired products 12c1 or 12c2
OH
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TMSOTf (0.1 equiv)
DCM, RT
O
O
BnO
DOI: 10.1039/D0OB00252F
in reasonably yields (Entries 5 and 6).
O
O
HO
BnO
STol
STol
NHTroc
7 (40%)
After examining the polyol substrates 10a10c, we examined
the sequential silylation and reductive etherification of
carbohydrate substrates 10d0g, which contained both primary
and secondary hydroxyl groups (Entries 710). Regardless the
position of the hydroxyl group, the silylation and reductive
etherification was fine and desired alkylation products 12d12g
were acquired in reasonable yields (7078%). A higher (20 °C)
reaction temperature was required for reductive etherification of
11e due to a hindered C4 hydroxyl group (Entry 8). For cyclic
arylidene or alkylidene protected substrates 10h10k, some
optimization at reaction temperature and amount of the TMSOTf
catalyst were required to prevent the transacetalation. Thus, the
silylation and PMHS reductive etherification of 2,3-O-
isopropylidene-thio-L-rhamnoside 10h with NapCHO and
PhCHO gave desired alkylation products 12h1 and 12h2 in 72%
and 88% yields, respectively, demonstrating that the dixolane-
type acetal protection was stable in present etherification
conditions (Entries 11 and 12). As for comparison, the reductive
etherification of 11h was repeated with Et3SiH (Entry 13). The
reaction gave desired product 12h2 in 60% yield, together
with~10% transilylation product. For sequential silylation and
reductive etherification of 2-azido-2-deoxy-thiogalactosamine
10i with NapCHO, a lower (70 °C) reaction temperature was
NHTroc
2 h
6
+
6 (50%)
(b)
NapCHO, TMSOTf
(0.1 equiv), DCM, RT
O
O
Nap
O
O
BnO
Ph
O
O
STol
STol
BnO
NHTroc
6 (43%)
NHTroc
2 h
8 (57%)
+
6
NO2
(c)
pNO2PhCHO
TMSOTf (0.1 equiv),
DCM, RT
O
O
BnO
Ph
O
S
STol
(6.14 ppm) H
O
O
BnO
O
NHTroc
18 h
STol
6
NHTroc
H (5.62 ppm)
R O
O2N
O
O
BnO
STol
NHTroc
9 (90%)
R:S = 5.7:1
+
6 (10%)
Scheme 2. (a) Treatment of 6 with TMSOf alone. (b) Treatment of 6 with TMSOTf in the
presence of NapCHO. (c) Treatment of 6 with TMSOTf in the presence of pNO2PhCHO.
were subjected to the sequential silylation and PMHS reductive
etherification protocol (Scheme 3, Table 2). Substrates 10a10g
contain various basic-labile protecting groups that may undergo
hydrolysis and/or migration in Williamson alkylation conditions.
In addition, it was necessary to probe the suitability of the
etherification procedure for some representative benzylidene or
isopropylidene protected substrates 10h10k.
In the general protocol, substrate 10 was treated with HMDS
to give TMS protected intermediate 11. After removing the
residual HMDS and its byproducts by the aqueous workup, crude
intermediate 11 was etherified with 1.1 equiv. of NapCHO (or
PhCHO) and 0.25 or 0.5 equiv. of PMHS at 20 to 70 °C in the
presence of TMSOTf. Nevertheless, for particular substrates, the
amount of TMSOTf had to be optimized.
(a) Sequential silylation and reductive etherification for hydroxyl alkylation
Aldehyde (equiv.)
PMHS (equiv.)
HMDS (1.2 equiv.)
TMSOTf (0.4 equiv.)
DCM, RT
work up with
NH4Cl(aq)
TMSOTf (equiv.)
R
ONap
OBn
R
OH
T
oC, DCM
R
OTMS
11a11k
Aldehyde: A = NapCHO; B = PhCHO
R
10a10k
(1.0 equiv)
12a12k
(b) Hydroxyl substrates 10a10k; TMS protected intermediate 11a11k; Alkylation products 12a12k
OR
OR
OR
TBDPSO
OAc
TBDPSO
O
C13H27
TsO
O
10c R = H;
10b R = H;
10a R = H;
The sequential silylation and PMHS reductive etherification of
1-acetyl-3-TBDP sn-glycerol 10a with NapCHO proceeded
smoothly to give desired alkylation product 12a yield via
silylated intermediate 11a (Table 2, entry 1). In the reaction
conditions, no acetyl group migration was observed and the
overall yield of 12a was 83%. As for comparison, the Et3SiH
reductive etherification of 11a was repeated with 0.1 and 0.2
equiv. of TMSOTf (Entries 2 and 3). The yields of the reactions
were lower than that given by the PMHS reductive etherification
due to the formation of bis(naphthylmethyl) ether [(Nap)2O].23
Gratifyingly, such a side product was not observed for the PMHS
reductive etherification of 11a.24
The reductive etherification was sensitive to steric factors.
This was evidenced by the silylation and PMHS reductive
etherification of 1-myristoyl-3-TBDP sn-glycerol 10b, whereas,
the yield of the reaction was just 42%. (Entry 4). Alkylation of
alkenyl substrate 10c is difficult in basic conditions due to the
competition of the epoxidation. However, with the PMHS
11b R = TMS
12b R = Nap
11c R = TMS
12c1 R = Bn 12c2 R = Nap
11a R = TMS
12a R = Nap
OR
OTBDPS
BnO
OR
OBz
O
OBz
O
O
RO
STol
NapO
BnO
BnO
BnO
OBz
STol
STol
10f R = H;
11f R = TMS
12f R = Bn
10e R = H;
11e R = TMS
12e R = Nap
10d R = H;
11d R = TMS
12d R = Nap
Ph
STol
OR
O
O
O
O
RO
BnO
RO
STol
O
O
O
STol
RO
NHTroc
N3
10g R = H
11g R = TMS
12g R = Bn
10h R = H
11h R = TMS
12h1 R = Nap; 12h2 R= Bn
10i R = H
11i R = TMS
12i R = Nap
Ph
O
O
Ph
O
O
10k R, R' = H
11k R, R' = TMS
12k1 R = Bn; R' = H
12k2 R = H; R' = Bn
12k3 R, R' = Bn
STol
O
RO
OR'
O
10j R, R' = H
11j R, R' = TMS
12j R = Bn; R' = H
STol
RO
OR'
reductive etherification method, 11c could be alkylated with Scheme 3. Sequential silylation and reductive etherification of substrates 10a10k.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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DOI: 10.1039/D0OB00252F
Table 2: Scope and limitations of sequential silylation and PMHS-mediated reductive etherification procedure
Entry
Substrate
RCHO (equiv.)
Silane (equiv.)
TMSOTf (equiv.)
T (oC)
Product (%)
1
2
10a
10a
10a
10b
10c
10c
10d
10e
10f
10g
10h
10h
10h
10i
NapCHO (1.1)
NapCHO (1.1)
NapCHO (1.1)
NapCHO (1.5)
PhCHO (1.1)
NapCHO (1.1)
NapCHO (1.1)
NapCHO (1.1)
NapCHO (1.1)
PhCHO (1.1)
NapCHO (1.1)
PhCHO (1.1)
PhCHO (1.1)
NapCHO (1.1)
NapCHO (1.1)
PhCHO (1.1)
PhCHO (1.1)
PMHS (0.25)
Et3SiH (1.2)
Et3SiH (1.2)
PMHS (0.25)
PMHS (0.25)
PMHS (0.25)
PMHS (0.5)
PMHS (0.25)
PMHS (0.25)
PMHS (0.25)
PMHS (0.25)
PMHS (0.25)
Et3SiH (1.2)
PMHS (0.5)
PMHS (0.5)
PMHS (0.25)
PMHS (0.5)

















30
30
30
30
30
30
30
20
30
30
30
30
30
70
70
30
70
12a (83)
12a (62)a
12a (77)b
12b (42)
3
4
5
12c1 (78)
6
12c2 (86)
7
12d (78)
8
12e (73)
9
12f (75)
10
11
12
13
14
15
16
17
12g (70)d
12h1 (72)
12h2 (88)
12h2 (60)c
No reaction
12i (85)
10i
10j
10k
12j (70)d
12k1, 12k2, 12k3 (73)d
a
b
c
3% (Nap)2O was obtained. 10% (Nap)2O ether was obtained. 5% Transilylation product was isolated. d THF was used as a solvent for HMDS-based silylation. e
Ratio of 12k1, 12k2, and 12k3 = 3:5:1.
applied to prevent the transacetalation (Entry 14). However, the coupled with the one-pot protecting-group manipulation via a
reaction did not proceed in the presence of 0.2 equiv. of TMSOTf. workup procedure.
This might be attributable to the inherent basicity of the azido
Scheme 4a depicts the sequential silylation and one-pot
group, which would attenuate the catalytic ability of TMSOTf.25- preparation of 6-hydroxyl and 4-hydroxyl N-Troc protected
27
After some experimentations, 1.0 equiv. of TMSOTf was thioglucosamine acceptors 17 and 18 from N-Troc
found effective for triggering the reaction (Entry 15). As such, thioglucosamine 13. The reaction commenced with the silylation
desired alkylation product 12i was obtained in 85% yield. of 13 in THF to give per-O-TMS protected thioglucosamine 16,
Interestingly, no sign of the transacetalation occurred for 12i in which was the feedstock for one-pot protecting group
such acidic conditions, which may be attributable to the lower manipulation. The one-pot reaction started with the
reaction temperature.
benzylidenation of 16 with PhCHO to give benzylidene
In previous studies, the etherification of a 2,3-di-O-TMS protected thioglucosamine 1a, which was subjected to the PMHS
protected glucoside gave a C3 alkylation product in excellent reductive etherification with a supplementary dose of PhCHO
regioselectivity.7,14 It was thus of interest to determine whether and 0.25 equiv. of PMHS to give benzylated product 6. The one-
our new etherification method exhibited similar selectivity. Thus, pot benzylidenation and reductive etherification was performed
10j was taken to silylation to give 2,3-di-O-TMS thioglucoside at 30 °C. Subsequent reductive cleavage of the benzylidene
11j. Subsequent PMHS reductive etherification of thioglucoside group of 6 was envisaged to enable the access of 6-hydroxyl
11j with 1.1 equiv. of PhCHO at 30 °C afforded 3-O-Bn acceptor 17 or 4-hydroxyl acceptor 18. Thus, treatment of 6 with
protected thioglucoside 12j in 70% yield as the sole isomer with borane-THF (BH3.THF) and TMSOTf furnished 6-hydroxyl
no 2-O-alkylation and 2,3-O-dialkylation products. However, acceptor 17.32 On the other hand, treatment of 6 with Et3SiH and
similar regioselectivity was not observed for thiogalactosyl trifluoroacetic acid (TFA) –20 °C acquired 4-hydroxyl acceptor
substrate 10k that containing a D-galacto skeleton (Entry 17). 18.33,34 The overall yields for 17 and 18 over 4 reaction steps are
The reaction resulted in a mixture of 3-O-alkylation 12k1, 2-O- 45% and 50%, respectively. In the previous one-pot preparation
alkylation 12k2, and dialkylation 12k3 products in a 3:5:1 ratio.28 of 18, the overall yield was 33%.18
Next, we examined the preparation of 2-azido-2-deoxy-
1.3 Sequential Silylation and One-Pot Protection Group
Manipulation
thiogalactosamine acceptor 21 from unprotected 2-azido-2-
deoxythiogalactosamine 14 based on the silylation and one-pot
protecting group manipulation strategy (Scheme 4b). Thus, 2-
azido-thiogalactosamine 14 was subjected to the HMDS
silylation to give per-O-TMS protected 2-azido-2-
deoxythiogalactosamine 19. After the workup, crude
intermediate 19 was reacted with PhCHO at -30 °C to give
Based on the PMHS reductive etherification method, we
developed the one-pot protecting-group manipulation protocols
for unprotected thioglycoside substrates 13,29 14,30 and 15
(Schemes 4a4c).31 To simplify the procedure and avoid the need
to purify the TMS glycosyl substrate, the silylation step was
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ARTICLE
benzylidene intermediate 11i. Subsequent PMHS reductive
etherification of 11i with a supplementary dose of PhCHO and
0.3 equiv. of PMHS furnished 2-azido-3-O-benzyl-4,6-O-
benzylidene-thiogalactoside 20. Unlike the above reductive
etherification of 11i with NapCHO in entry 15 of Table 2, a
higher (40 °C) temperature was allowed for the reductive
etherification with PhCHO because the latter would not suffer
from the transacetalation. Reductive acetal cleavage of 20 with
Et3SiH and TFA completed the preparation of 4-hydroxyl
acceptor 21 in good 60% overall yield (4 steps from 14).
After the one-pot preparation of glycosamine acceptors 17, 18,
and 21, the sequential silylation and one-pot protecting group
manipulation protocol was applied for preparation of
thioglucoside donor 24 from unprotected thioglucoside 15
(Scheme 4c). Thus, the HMDS-based silylation of unprotected
thioglucoside 15 afforded per-O-TMS-protected thioglucoside
22. In contrast to the silylation of substrates 13 and 14, a large
excess of HMDS (5 equiv.) was required to effect the conversion
of 15 to 22. We also note that the C2 hydroxyl of thioglucoside
15 was much less reactive than the C3 and C4 hydroxyls in
silylation. Subsequent benzylidenation of 22 with PhCHO at 30
°C afforded benzylidene intermediate 11j, which was subjected
to the PMHS reductive etherification with a supplementary
amount of PhCHO at 30 °C to produce alkylation product 23.
Final acetylation of 23 with acetic anhydride (Ac2O) furnished
desired thioglucosyl donor 24 in 52% yield (over 4 reaction steps
from 15). ln the previous one-pot protocol, this acetylation was
a two-step process, comprising a desilylation and base-promoted
acetylation.17
View Article Online
DOI: 10.1039/D0OB00252F
(a)
HMDS (2.4 eq),
TMSOTf (0.8 eq),
THF and work up
OTMS
O
TMSO
TMSO
PhCHO (1.1 eq) MS,
TMSOTf (0.1 eq), DCM
STol
NHTroc
RT
-30 o
C
16
OH
O
HO
HO
STol
O
O
Ph
O
NHTroc
STol
13
TMSO
NHTroc
3-O-TMS thioglucosamine 1a
PhCHO (1.0 eq)
PMHS (0.25 eq)
TMSOTf (0.1 eq), DCM
-30 o
C
O
Ph
O
O
STol
BnO
NHTroc
Et3SiH (10 eq),
TFA (1 eq), DCM
BH3-THF (5 eq)
TMSOTf (0.2 eq),
DCM
OH
6
RT
-20 o
C
OBn
O
O
HO
BnO
BnO
BnO
STol
STol
NHTroc
NHTroc
17 (45% over 4 steps from 13, 1.5 day)
18 (50% over 4 steps from 13, 1 day)
(b)
OTMS
O
TMSO
TMSO
PhCHO (1.2 eq)
TMSOTf (0.15 eq)
MS, DCM
HMDS (2.5 eq)
TMSOTf (0.9 eq)
THF and work up
RT
-30 o
C
N3
STol
19
Ph
OH
OH
O
O
O
STol
HO
O
N3
TMSO
14
Ph
STol
N3
11i
O
-40 o
C
O
Et3SiH (10 eq),
TFA (4.5 eq), DCM
PhCHO (1.1 eq)
PMHS (0.3 eq)
TMSOTf (0.45 eq)
DCM
O
BnO
STol
N3
OBn
-40 to -20 o
C
HO
20
O
BnO
STol
N3
In above one-pot reactions, the TMS protected intermediates
were not stable in acidic conditions; and thus, they may have
been partially hydrolysis in the TLC plate. Therefore, in
monitoring the progress of the one-pot reaction by TLC, some
rationalization was required in result interpretation.
21 (60% over 4 steps
from 14, 1 day)
(c)
OTMS
O
PhCHO (1.0 eq)
TMSOTf (0.1 eq)
MS, DCM
HMDS (5.0 eq)
TMSOTf (0.4 eq)
THF and work up
TMSO
TMSO
STol
OTMS
-30 o
C
RT
22
OH
O
O
TMSO
O
Ph
Conclusions
HO
HO
O
STol
STol
OH
OTMS
In summary, we have developed a new reductive etherification
procedure for carbohydrate substrates. The new procedure uses
polymethylhydrosiloxane (PMHS) as a sub-stoichiometric
reducing agent, which prevents the transilylation side reaction.
Based on the PMHS reductive etherification procedure, several
sequential silylation and one-pot protecting group manipulation
protocols have been developed. In addition to the method
development, we clarified the causes of the transacetalation side
reaction that occurred during the etherification of cyclic acetal
protected glycosyl substrates. This information will be useful
when using the silane based reductive etherification procedure to
protect the polyol substrates.
15
11j
-30 o
C
PhCHO (1.0 eq)
PMHS (0.25 eq)
TMSOTf (0.1 eq)
DCM
O
O
BnO
Ph
O
Ac2O (1.0 equiv)
DCM
STol
-30 o
C
OTMS
23
O
O
BnO
Ph
O
STol
OAc
24 (52% over four
steps from 15, 1 day)
Scheme 4. One-pot protecting group manipulation of (a) unprotected N-Troc-
thioglucosamine 13, (b) 2-azido-2-deoxy-thiogalactoside 14, and (c) thioglucoside 15
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Journal Name
20 J. S. Yadav, B. V. S. Reddy, K. S. Shankar, T. Swamy,
Thanks are given to the Ministry of Science and Technology in
Taiwan (MOST) for financial support (Grant no. MOST 108-
2113-M-009-021), to the Centre for Advanced Instrumentation
for mass spectroscopy analyses and the National Chiao Tung
University for NMR spectroscopy services.
View Article Online
Tetrahedron, 2010, 51, 46-48.
DOI: 10.1039/D0OB00252F
21 S. Chandrasekhar, G. Chandrasekhar, B. N. Babu, K. Vijeender,
K. V. Reddy, Tetrahedron Lett. 2004, 45, 5497-5499.
22 M. Giordano, A. Iadonisi, Tetrahedron Lett. 2013, 54, 1550–
1552.
23 Due to the transilylation side reaction in Scheme 1 and similar
Rf values, we initially assumed that the side product of the
reactions in entries 2 and 3 was the transilylation product 4.
After isolation for NMR characterization, the side product was
(Nap)2O. Noteworthy, the reductive etherification of carbonyl
compounds is known to occur at RT (see ref 11 and 12d).
24 It should be noted that in previous PMHS reductive
etherification of aldehyde (ref 20), the acid catalyst was iodine
and the reaction was performed at RT.
25 P. Desai, K. Schildknegt, K. A. Agrios, C. Mossman, G. L.
Milligan, J. Aubé, J. Am. Chem. Soc. 2000, 122, 7226-7232.
(basic property of azide)
26 H.-L. Lee and J. Aubé, Tetrahedron, 2007, 63, 9007-9015.
(basic property of azide)
27 A. Murali, M. Puppala, B. Varghese, S. Baskaran, Eur. J. Org.
Chem. 2011, 5297–5302. (basic property of azide)
28 It has reported that isopropyl 4,6-O-benzyidlene-α-
galactoside, which has a similar structure to 10k, could be
alkylated at C3 position in Ref 7. The difference may be
attributed to their different anomeric configurations.
29 C. C. Lin, T. S. Hsu, K. C. Lu, I. T. Huang, J. Chin. Chem. Soc.
2000, 47, 921-928.
30 J. Kalikanda, Z. Li, J. Org. Chem. 2011, 76, 5207-5218.
31 K. K. T. Mong, K. S. Shiau, Y. H. Lin, K. C. Cheng, C. H. Lin, Org.
Biomol. Chem. 2015, 13, 11550-11560.
32 K. Daragics, P. Fugedi, Tetrahedron Lett. 2009, 50, 2914-2916.
33 M. P. DeNinno, J. B. Etienne, K. C. Duplantier, Tetrahedron
Lett. 1995, 36, 669-672.
Notes and references
‡
Supporting information for general PMHS reductive
etherification and one-pot protecting group manipulation
procedure, NMR spectroscopic data of 24, 79, 10a10k,
12a12k, 17, 18, 21, and 24 are available.
1
2
A. Demchenko, Org. Biomol. Chem. 2019, 17, 4934-4950.
S. Oscarson, Protective group strategies, in The organic
chemistry of sugars, ed. D. E. Levi and P. Fugedi, CRC, Taylor &
Francis, Boca Raton - London - New York, 2006, pp. 53–88.
S. M. Polyakova, A. V. Nizovtsev, R. A. Kuznetskiy, and N. V.
Bovin, Russ. Chem. Bull. 2015, 974–989.
K. Ágoston, H. Streicher and P. Fügedi, Tetrahedron:
Asymmetry, 2016, 27, 707–728.
S. S. Kulkarni, C. C. Wang, N. M. Sabbavarapu, A. R. Podilapu,
P. H. Liao, S. C. Hung, Chem. Rev. 2018, 118, 8025-8104 and
references cited therein.
3
4
5
6
7
8
9
C. C. Wang, J. C. Lee, S. Y. Luo, S. S. Kulkarni, Y. W. Huang, C.
C. Lee, K. L. Chang, S. C. Hung, Nature, 2007, 446, 896-899.
C. C. Wang, M. M. L. Zulueta, S.-C. Hung, Chimia, 2011, 65, 54-
58.
A. Francais, D. Urban, J. M. Beau, Angew. Chem. Int. Ed., 2007,
46, 8662-8665.
Z. Huo, D. Ding, Y. Zhang, N. Lei, G. Gu, J. Gao, Z. Guo, and F.
Cai, J. Carbohydr. Chem., 2018, 37, 327-346 and reference
cited therein.
34 Y. Yoneda, H. Hettegger, T. Rosenau, T. Kawada,
ChemistrySelect. 2016, 1, 5715-5720.
10 G. Despras, D. Urban, B. Vauzeillesa, J.-M. Beau, Chem.
Commun., 2014, 50, 1067-1069.
11 M. P. Doyle, D. J. DeBruyn, D. A. Kooistra, J. Am. Chem. Soc.
1972, 94, 3659-3661.
12 a) A. Pelosi, D. Lanari, A. Temperini, M. Curini, O. Rosati, Adv.
Synth. Catal. 2019, 361, 4527-4539. b) C. Zhao, C. A. Sojdak,
W. Myint, D. Seidel, J. Am. Chem. Soc., 2017, 139,
10224−10227. c) J. S. Ruso, N. Rajendiran, N. S. Kumaran, G.
Manickam, J. S. Chem. Soc., 2016, 20, 330-335. d) B. A. Gellert,
N. Kahlcke, M. Feurer, S. Roth, Chem. Eur. J., 2011, 17, 12203-
12209. e) S. Hatakeyama, H. Mori, K. Kitano, H. Yamada, M.
Nishizawa, Tetrahedron Lett. 1994, 35, 4367-4370. f) J.-I. Kato,
N. Iwasawa, T. Mukaiyama, Chem. Lett., 1985, 14, 743-746.
13 L. Huang, X. Huang, Chem. Eur. J., 2007, 13, 529-540.
14 A. A. Joseph, V. P. Verma, X. Y. Liu, C. H. Wu, V. M. D
hurandhare, C. C. Wang, Eur. J. Org. Chem., 2012, 744-753.
15 The identity of 3 could be inferred from the naphthylidene
proton signal at ca. 5.75 ppm and detection of its molecular
ion by the mass spectrometry. 3 was also prepared separately
1
and the corresponding H NMR spectrum was acquired for
comparison (See NMR spectrum of 3 in SI).
16 In previous protocol, the basic HMDS by-products were
removed by purging with N2, but we found that the workup
procedure (washing NH4Cl(aq)) was more reliable for removal
of the by-products, which if present might affect the acid-
catalyzed etherification.
17 Protocol using -86 oC temperature for the etherification
reaction: C. C. Wang, S. S. Kulkarni, J.-C. Lee, S.-Y. Luo, S.-C.
Hung, Nature Protocols, 2008, 3, 97-112.
18 R. Enugala, L, C. R. Carvalho, M. Mauel, B. Marques, Synlett,
2010, 2711-2716.
19 N. J. Lawreance, M. D. Drew, S. M. Bushell, J. Chem. Soc. Perkin
Trans. 1, 1999, 3381-3391.
6 | J. Name., 2012, 00, 1-3
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