Stannous chloride as a low toxicity and extremely cheap catalyst for regio-/site-selective acylation with unusually broad substrate scope

Article abstract of DOI:10.1039/d0gc02739a

This work reports stannous chloride (SnCl2)-catalyzed regio-/site-selective acylation with unusually broad substrate scope. In addition to 1,2- and 1,3-diols and glycosides containing cis-vicinal diol, the substrate scope also includes glycosides without cis-vicinal diol. For such a substrate scope, usually, only methods using stoichiometric amounts of organotin reagents can lead to the same protection pattern with high selectivities and highly isolated yields (84-97% in most cases). Therefore, SnCl2, as a low toxicity and extremely cheap reagent, should be the best catalyst for regio-/site-selective acylation compared with any previously reported reagents. This journal is

Full text of DOI:10.1039/d0gc02739a

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DOI: 10.1039/D0GC02739A
ARTICLE
Stannous Chloride as a Low-toxic and Extremely Cheap Catalyst
for Regio/Site-Selective Acylation with Unusually Broad Substrate
Scope
Received 00th January 20xx,
Accepted 00th January 20xx
Jian Lv, a Jian-Cheng Yu, a Guang-Jing Feng, a Tao Luoa and Hai Dong*a,b
DOI: 10.1039/x0xx00000x
This work reports stannous chloride (SnCl2)-catalyzed regio/site-selective acylation with unusually broad substrate scope. In
addition to 1,2- and 1,3-diols and glycosides containing cis-vicinal diol, the substrate scope also includes glycosides without
containing cis-vicinal diol. For such a substrate scope, usually, only methods using stoichiometric amounts of organotin
reagents can lead to the same protection pattern with high selectivities and highly isolated yields (84 – 97% in most cases).
Therefore, SnCl2, as a low-toxic and extremely cheap reagent, should be the best catalyst for regio/site-selective acylation
compared with any previously reported reagents.
complex structures (Figure 1). In addition, some of these
catalysts are applicable to substrates containing cis-diol (Figure
1a),6c,7a,g another are applicable to substrates containing trans-
Introduction
Regio/site-selective protection strategies can identify multiple
hydroxyl groups with similar activity, avoiding a large number of
tedious and time-consuming hydroxyl protection and
deprotection processes, thereby reducing the synthetic steps of
building blocks in carbohydrate chemistry.1 Organotin reagents
have been playing key roles in selective protection strategies for
decades.2,3 By the use of stoichiometric amounts of organotin
reagents, good selectivities could be obtained over a broad
substrate scope, including 1,2- and 1,3-diols, glycosides
containing cis-vicinal diol and glycosides without containing cis-
vicinal diol.3 The protection pattern was summarized that the
primary and equatorial hydroxyl groups showed good selectivity
for substrates containing 1,2-diol, 1,3-diol, and cis-diol, and the
equatorial hydroxyl groups adjacent to the axial substituents
showed good selectivity for substrates containing trans-diol,
one adjacent substituent being axial and the other being
equatorial. However, due to the potentially inherently toxicity
of organotins, protection strategies (focusing on acylation)
using catalytic amounts of organotin4 and lower-toxic
alternatives, including heavy metal-based complexes,5 chiral
catalysts6 and other metallic/nonmetallic catalysts7 and
reagents,8 have been developed in succession. In most cases,
researchers have focused on controlling site-selectivities, and
been less concerned about whether the used catalysts are
cheap and readily available so that these catalysts often have
diol (Figure 1b),6a,b,7c and even some of them are only applicable
to very specific substrates (Figure 1c).7b,d-f There are only few
catalysts that are applicable to both substrates containing cis-
diol and substrates containing trans-diol (Figure 1d) except for
the methods using stoichiometric amounts of organotin
reagents.5a,b,8a These may be the reasons why toxic organotin
reagents are still often used in laboratories to date.2a-e Our
group has been committed to developing protection strategies
where the used reagents are inexpensive and environmental-
friendly.9 Particularly, [Fe(acac)3] (acac = acetylacetonate), a
green and inexpensive catalyst for selective acylation of 1,2-
diols, 1,3-diols, and glycosides containing cis-vicinal diol, was
identified by us recently.10 After that, it was further found that
FeCl3 and acetylacetone could be used as a catalytic system to
catalyze selective acylation.11 These results encouraged us to
extensively investigate catalytic systems composed of various
metal salts and acylacetone ligands.12 To our delight, during
these investigations, we occasionally found that stannous
chloride (SnCl2) was a perfect catalyst for selective acylation
(Figure 1e). A systematic investigation on SnCl2-catalyzed
selective acylation has been addressed in this study. The results
indicated that SnCl2 showed similar/higher catalytic activity
to/than organotins in acylation. SnCl2 could not only catalyze
the selective acylation of 1,2-diols, 1,3-diols, and glycosides
containing cis-diol, but also catalyze the selective acylation of
glycosides containing trans-diol, leading to the same protection
pattern with high selectivities and highly isolated yields as that
in methods using stoichiometric amounts of organotin
reagents. Furthermore, the structure of SnCl2 is simpler than
those of organotins so that SnCl2 is more inexpensive and easily
acquired. Therefore, for the first time, we have found a low-
toxic reagent for acylation, SnCl2, which is not only possibly
more inexpensive than organotin reagents, but also comparable
a. Key laboratory of Material Chemistry for Energy Conversion and Storage, Ministry
of Education, School of Chemistry & Chemical Engineering, Huazhong University
of Science & Technology, Luoyu Road 1037, 430074 Wuhan, PR China. Tel.: +86
2787793243; Fax: +86 2787793242; E-mail: hdong@mail.hust.edu.cn.
b. Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica,, Huazhong
University of Science & Technology, Wuhan, PR China.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Page 2 of 7
ARTICLE
Journal Name
Table 1 Comparison of results achieved under various conditionsa
to organotin reagents in other aspects, including selectivity,
substrate scope, and reaction efficiency.
View Article Online
DOI: 10.1039/D0GC02739A
O
O
O
O
O
O
O
Ph
Ph
Ph
Ph
O
O
O
O
O
Cat, BzCl, base
MeCN, r.t.
+
+
OMe
HO
HO
OBz
2a
BzO
2b
BzO
HO
HO
OBz
2c
OMe
OMe
OMe
1
HO
Entry
Various Conditions
Base and Catalyst (equiv)
b Ratio
O
O
HO
HO
HO
(2a/2b/2c/1)
48/6/2/44
79/15/0/6
78/5/3/14
92/3/0/5
96/4/0/0
29/4/0/67
31/4/0/65
95/4/0/1
89/5/0/6
84/3/0/13
84/4/0/12
84/4/6/6
43/6/38/1
3
carbohydrates containing
carbohydrates containing
trans-diol
cis-diol
1
2
3
4
5
6
7
8
9
10
11c
12
13
DIPEA (1.9), FeCl3/Hacac (1/3, 0.1), 4h
DIPEA (1.9), BiCl3/Hacac (1/3, 0.1), 4h
DIPEA (1.9), MnCl2/Hacac (1/2, 0.1), 4h
DIPEA (1.9), SnCl2/Hacac (1/2, 0.1), 4h
DIPEA (1.9), SnCl2 (0.1), 1h
a)
catalysts for carbohydrates containing cis-diol
OH
HO
O
B
N
O
N
N
N
B
N
N
H2
DIPEA (1.9), Hacac (0.2), 4h
DIPEA (1.9), 4h
DIPEA (1.5), SnCl2 (0.05), 1h
OMe
2013
2019
,
Nature Chem.
5, 790.
,
J. Am. Chem. Soc.
Org. Lett.
2011, 133, 3724.
21, 3789.
DIPEA (1.2), SnCl2 (0.05), 4h
b)
catalysts for carbohydrates containing trans-diol
DIPEA (1.5), SnCl2▪2H2O (0.05), 1h
DIPEA (1.8), SnCl2▪2H2O (0.05), 1h
TEA (1.5), SnCl2 (0.05), 4h
O
N
H
N
S

Leu-Asp-NH2
Ph
N
Ac-Val-Pro-Phe
N
O
N
N
(R or S)-BTM
Pyridine (1.5), SnCl2 (0.05), 4h
N
N
N
2017
J. Am. Chem. Soc.
139, 4346., Angew. Chem.,
2019
,
14
DABCO (1.5), SnCl2 (0.05), 4h
61/2/15/2
2
2016
Chem. Eur. J.
, 22, 5914.
Int. Ed.
, 58, 9542.
15
16
17d
DBU (1.5), SnCl2 (0.05), 4h
K2CO3 (1.5), SnCl2 (0.05), 4h
DIPEA (1.5), SnCl2 (0.05), 8h
14/4/2/80
63/7/0/30
58/21/9/1
2
c)
catalysts for specific carbohydrate substrates
O
O
H
H
N
N
O
O
N
O
O
NH
HN
N
18d
DIPEA (1.5), 8h
55/27/9/9
a
Reaction conditions: substrate 1 (0.1mmol), BzCl (1.2 equiv), CH3CN (0.5
2007
, 129, 12890.; J. Org. Chem.
2012
, 77, 7850.
J. Am. Chem. Soc.
mL), rt. b Ratios determined by 1H NMR. c BzCl (1.4 equiv). d Bz2O (1.2 equiv),
2015
2017
Angew. Chem. Int. Ed.
, 54, 6177.; Org. Lett. , 19, 3099.
40 ℃.
d) catalysts for carbohydrates containing either cis-diol or trans-diol
N
We initially tested the system composed of 0.1 equiv of FeCl3
and 0.3 equiv of acetylaceton in the presence of 1.9 equiv of
DIPEA and 1.2 equiv of BzCl (Entry 1). Although the result
showed a good selectivity (2a/2b/2c: 48/6/2), a large amount
of 1 (44%) indicated low or no catalytic activity of this system.
Interestingly, when BiCl3 was used instead of FeCl3, the
conversion rate was greatly improved (94%) at the cost of
selectivity (2a/2b/2c: 79/15/0, Entry 2). When MnCl2 was used,
a good selectivity (2a/2b/2c: 78/5/3) but still an unsatisfactory
conversion rate (86%) was obtained (Entry 3). Encouragingly,
when SnCl2 was used, an excellent selectivity (2a/2b/2c:
92/3/0) and a satisfactory conversion rate (95%) were observed
(Entry 4). To our surprise, a better result was obtained in the
absence of the acetylacetone ligand (2a/2b/2c/1: 96/4/0/0,
Entry 5). As expected, the absence of SnCl2 led to low reactivity
of the benzoylation (Entries 6 and 7). These results indicated
that acetylacetone used as the ligand was superfluous while
SnCl2 was used as the catalyst. The excellent result was
maintained when 0.05 equiv of SnCl2 and 1.5 equiv of DIPEA
were used (2a/2b/2c/1: 95/4/0/1, Entry 8). The use of 1.2 equiv
of DIPEA led to a slight decrease in the conversion rate
(89/5/0/6), and prolonging the reaction time (4 h in Entry 9)
could not further increase this conversion rate. We wondered if
the stannous chloride dihydrate (SnCl2▪2H2O) could be used
instead of the stannous chloride. The result indicated that the
conversion rate was reduced from 99% (Entry 8) to 87% (Entry
10), but the selectivity still remained (95/4 in Entry 8, 84/3 in
BF4
O
O
N
N
N
N
N
OTBPS
Cu(OTf)2
or CuCl2
Ph
Ph
2014
, 20, 5013.
, 15, 6178.
2016
Chem. Eur. J.
2013
Chem. Eur. J.
,
Org. Lett.
22, 7403.
This study
e)
Sn
1 - 5 mol%
Cl
Cl
Green, Inexpensive, Readily acquired,
High selectivity, Broad substrate scope
Figure 1 Comparison of various methods for selective acylation.
Results and discussion
Optimization of reaction conditions.
Based on the investigation of catalytic systems composed of
various metal salts and acetylacetone, we tried to screen out a
catalytic system that can catalyze the selective acylation of
substrates containing trans-diol. For this purpose, the methyl-
4,6-benzylidene-α-D-glucopyranoside 1 which contains trans-
diol was used as a substrate in benzoylation to explore feasible
reaction conditions (Table 1). The ratio of 2-benzoylated
product 2a, 3-benzoylated product 2b, 2,3-di-benzoylated
product 2c and residual starting material 1 indicates the
selectivity and the reactivity of this benzoylation (Figure S1 in
SI).
2 | J. Name., 2012, 00, 1-3
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ARTICLE
Entry 10). We then tried to eliminate the adverse effects caused organotin reagents: an axial group and an equatorial group are
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by crystal water of SnCl2▪2H2O by increasing the amount of adjacent to the trans-diol moiety, which iDsOthI:e10k.e10y3t9o/Ds0eGleCc0t2iv73it9yA,
DIPEA and BzCl simultaneously, but failed (Entry 11). We gave and the hydroxyl group adjacent to the axial group is selectively
up studying the application of SnCl2▪2H2O since the prices of protected.3 It can be seen, benzoylation of substrates 1, 7, 9, 11,
SnCl2▪2H2O and SnCl2 are almost the same. Various bases, 13, 15, 17 and 19 by this method led to excellent yields of the
including TEA, pyridine, DABCO, DBU and K2CO3, were also selectively benzoylated products 2a, 8, 10, 12, 14, 16, 18 and 20
tested in this benzoylation with 0.05 equiv of SnCl2 (Entries 12 - (83 - 93%, entries 1, 4 -10 in Table 2), and benzoylation of
16). A relatively good result was also obtained with TEA as the substrates 3 and 5 led to poor selectivies since two equatorial
base (2a/2b/2c/1: 84/4/6/6, Entry 12). The other results or axial groups are adjacent to their trans-diol moieties (Entries
showed poor selectivities and/or poor conversion rates. When 2 and 3 in Table 2). However, an interesting result was that SnCl2
Bz2O was used as the acylation reagent instead of BzCl, the showed no or low catalytic activity for the acylation of 3, but
reaction had to proceed at 40℃due to the low activity of Bz2O, showed high catalytic activity for the acylation of 5, indicating
but the poor selectivity was obtained regardless of the presence that the adjacent axial group plays a key role for the catalytic
of SnCl2, indicating that SnCl2 did not show significant catalytic activity. It is worth mentioning that these satisfactory selective
activity in this reaction (Entries 17 and 18). We also screened acylation results for substrates containing a trans-diol have
several commonly used solvents and identified acetonitrile never been achieved using iron-based catalytic systems.10-12a
(MeCN) as the optimal solvent under the catalyst loading (Table Compared with organotins and catalysts shown in Figure 1d,
S1 and Figure S2 in SI).
Evaluation of this method using various substrates.
this method has advantages in terms of substrate scope,
product yield and reaction efficiency (Table S2 in SI).4,5a,b,8a
Table 2 SnCl2-catalyzed regioselective benzoylation of substrates containing trans-
diola
Scheme 1 SnCl2-catalyzed regioselective benzoylation of substrates containing cis-
, 1,2-, or 1,3-diola
HO OTBS
HO OTBS
O
HO OTBS
O
HO OTBS
O
Entry
1
Substrate
Product
Isolated Yields %
92 (855b, 835a)
O
O
O
OMe
STol
Ph
Ph
Ph
Si-Pr
BzO
O
O
O
BzO
BzO
BzO
O
HO
HO
OMe
2a
OMe
HO
HO
HO
1
HO
HO
BzO
OMe
22: 90%
(82%b, 78%c, 97%d)
24
: 95%
26
: 96%
28
: 91%
(85%b, 76%c, 92%d) (89%b, 89%c, 94%d) (93%b, 84%c, 84%d)
O
O
No or poor
selectivity
Ph
Low conversion
rateb
O
2
3
OMe
HO
HO OTBS
OR2
O
OBn
O
HO
3
HO
O
Ph
O
O
SPh
Ph
32a
32b
: R1 = Bz, R2 = H, 75%
R1O
BzO
34
6a: R1=Bz R2=H
6b: R2=Bz R1=H
95 (6a/6b = 65/35)
BzO
HO
O
O
O
BnO
: 93%
O
: R2 = Bz, R1 = H, 21%
OMe
OMe
O
O
(81%/13%b, 70%/25%c, 89%/-d)
30
: 95%
HO
R2O
5
OMe
6
(93%b, 66%c, 93%d)
HO
R1O
O
OMe
OCH3
OH
OBn
HO
OTBS
O
OTBS
O
Ph
Ph
HO
BzO
H3C
O
O
O
O
O
O
O
OMe
4
5
86 (815b)
93
SPh
O
O
BzO
HO
OMe
OMe
BnO
BzO
OBz
HO
OH
OH
HO
40
7
8
HO
HO
36
: 91%
38
: 90%
: 90%
(80%b, 74%c, 93%d)
(87%b, 82%c, 85%d)
Ph
Ph
O
O
O
OCH3
OBz
OBz
O
O
OBz
HO
S
S
H3C
HO
O
O
HO
BnO
BzO
O
HO
HO
BnO
O
OMe
HO
Ph
9
HO
OMe
10
BnO
BzO
42
BnO
OMe
OH
BnO
BnO
Ph
O
: 94%
46
: 84%
44
: 92%
48
: 73%
(86%b, 82%c, 95%d)
(-b, -c, 93%d)
O
O
O
6
7
87
90
O
O
STol
STol
12
BnO
BzO
OR1
R2O
BzO
HO
OBz
OBz
O
11
HO
HO
Ph
HO
HO
BnO
HO
52
a b
94% (
/
= 88/12)
Ph
Ph
: 81%
(84%b, 84%c, -d)
OMe
54a: R1 = Bz, R2 = H
: R2 = Bz, R1 = H
50
: 83%
O
O
O
O
56
: 84%
(81%b, 78%c, 91%d)
(-b, -c, 83%d)
54b
O
O
SPh
SPh
HO
BzO
HO 13
HO 14
OBz
OBz
HO
HO
OH
TBSO
TBSO
OBn
O
OBn
O
BzO
OBz
O
PhO
HO
HO
HO
BzO
58
: 89%
60
: 87%
8
9
89
85
62: 78%e
(81%b, 85%c, 80%d) (76%b, 77%c, 82%d)
15
16
SPh
SPh
BnO
BnO
OBn
O
OBn
O
a Reaction conditions: substrates 21, 23, … 59, 61 (0.1 - 0.2 mmol), SnCl2 (0.05
equiv), DIPEA (1.2 -1.5 equiv), BzCl (1.2 - 1.5 equiv), MeCN (0.5 - 1.0 mL), 1 -
2 h, rt. b Fe(acac)3 (0.1 equiv), DIPEA (1.2 equiv), BzCl (1.2 equiv), 2 – 8 h, rt
(ref 10). c FeCl3 (0.1 equiv), acetylacetone [Hacac] (0.31 equiv), DIPEA (1.9
HO
HO
HO
BzO
17
OR
18
OR
OMe
OMe
20a: R=TBS 83
(845a)
20b: R=TBDPS 87
O
O
HO
HO
HO
HO
10
20
d
19
OMe
equiv), BzCl (1.5 equiv), 4 – 12 h, rt (ref 11). FeCl3 (0.1 equiv),
HO
BzO
OMe
benzoyltrifluoroacetone [Hbtfa] (0.2 equiv), K2CO3 or DIPEA (1.9 equiv), BzCl
(1.5 equiv), 1 – 12 h, rt (ref 12a). e DIPEA (2.5 equiv) and BzCl (2.5 equiv) were
used.
a Reaction conditions: substrate (0.1 - 0.2 mmol), SnCl2 (0.05 equiv), DIPEA
(1.5 equiv), BzCl (1.2 - 1.5 equiv), MeCN (0.5 - 1.0 mL), 1 - 2 h, rt. b No or low
catalytic activity.
This method was further applied to the selective benzoylation
of substrates containing a cis-, 1,2-, or 1,3-diol moiety (scheme
1). The results are better/similar than/to those we previously
reported in methods using iron (III)-catalysts.10-12a Furthermore,
SnCl2 showed the highest catalytic activity and this method
With the optimal condition (Entry 8 in Table 1) in hand, we
further evaluated this method using glycoside substrates
containing a trans-diol moiety in this benzoylation (Table 2). The
results showed a protection pattern that is identical to the
protection pattern when using stoichiometric amounts of
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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ARTICLE
Journal Name
chloroformates (CbzCl and FmocCl). In almost all cases, the
showed the highest reaction efficiency. For almost all substrates
containing a cis-diol moiety, the products in which the
equatorial hydroxyl group of the cis-diol moiety is benzoylated
were obtained in 90 - 96% yields. For the substrates containing
1,2-, or 1,3-diol, the primary hydroxyl groups were selectively
benzoylated. The manno-type substrate showed a relatively
poor selectivity (32a/32b: 75/21%) in this method, which is
likely due to acyl group migration, the benzoate group migrating
from the equatorial position to the axial position.13 Glycerol
containing two primary hydroxyl groups produced a mixture of
mono- and di-substituted products under the above conditions.
Therefore, we used 2.5 equiv of DIPEA and 2.5 equiv of BzCl in
this reaction, obtaining dibenzoylated product 62 in 78% yield.
desired products were obtained in high yields (85V–iew97Ar%tic)le. OOnnlinlye
DOI: 10.1039/D0GC02739A
the reaction of substrate 1 with the long-chain aliphatic
carboxylic acid chloride led to a relatively poor yield of 2-
acylated product 2g (69%). The reaction of substrates 1 or 23
with PivCl required 2.0 equiv of DIPEA and 2.0 equiv of PivCl for
a highly efficient acylation.
Scheme 3 SnCl2-catalyzed selective acylation of 1 and 23 with various acylation
reagentsa
O
O
Ph
Ph
O
O
O
O
1
OMe
HO
HO
HO
RO
SnCl2 (5.0 mol %)
DIPEA, RCl
OMe
2d-2i
HO OTBS
O
HO
HO OTBS
CH3CN
O
OMe
23
OMe
RO
HO
HO
24a-24f
Scheme 2 SnCl2-catalyzed site-selective benzoylation of unprotected methyl
glycosides
R =
I
O
O
O
2e,
OH
OBz
O
b
2d,
24a,
89%
97%
2f
, 91%
90%
24b,
O
a
HO
HO
HO
HO
b
96%
24c
, 96%
63
OMe
64
78%
(-c, -d, -e)
OH
OH
BzO
OMe
C15H31
O
OBz
O
O
O
O
HO
HO
HO
HO
O
b
OMe
OMe
66
2g, 69%c
O
2i
2h
, 85%
24f
, 89%
62%
(-c, -d, -e)
65
HO
OH
HO
24d
, 90%
24e
, 88%
, 94%
OH
O
HO
HO
HO
HO
HO
BzO
HO
BzO
a Reaction conditions: substrate (0.1 mmol), SnCl2 (0.05 equiv), DIPEA (1.5
equiv), RCl (1.5 equiv), MeCN (0.5 - 1.0 mL), 0.5 - 1 h, rt. b substrate (0.1
mmol), SnCl2 (0.05 equiv), DIPEA (2.0 equiv), PivCl (2.0 equiv), MeCN (0.5
mL), 0.5 h, rt. c 3-acylated product was isolated in 26% yield.
O
b
67
68
71%
(-c, -d, -e)
OH
OH
OMe
OMe
OH
O
OBz
O
a
OMe
69
OMe
70
OH
OH
94%
(80%c, 79%d, 93%e)
This method was also tested in large-scale reactions where the
amount of catalyst was reduced to 0.01 equivalent. Methyl 6-O-
TBDPS-α-D-glucopyranoside 19b (1.0 g) and methyl 6-O-TBS-β-
D-galactopyranoside 23 (580 mg) were reacted with 1.5 equiv of
BzCl in the presence of 0.01 equiv of SnCl2 and 1.5 equiv of
DIPEA in acetonitrile (10 mL) at room temperature for 1 h, giving
expected monobenzoylated products 20b and 24 in 83% and
93% yields respectively (Scheme 4). The reason why the 0.05
equiv of SnCl2 was used above is that the amount of catalyst is
too small to accurately weigh. However, this result indicated
that even the use of 0.01 equiv of SnCl2 was effective in
catalyzing this regio/site-selective acylation.
HO
BzO
OH
O
OH
O
a
HO
HO
HO
BzO
71
OMe
72
OMe
89%
(76%c, 72%d, 96%e)
a
Reaction conditions: Substrate (0.2 mmol), SnCl2 (0.05 equiv), DIPEA (2.5
equiv), BzCl (2.5 equiv), MeCN (1.0 mL), 1 h, rt. b Substrate (0.2 mmol), SnCl2
(0.05 equiv), DIPEA (1.5 equiv), BzCl (1.5 equiv), MeCN (1.0 mL), 0.5 - 1 h, rt.
c Fe(acac)3 (0.1 equiv), DIPEA (4 equiv), BzCl (4 equiv), MeCN (1.0 mL), 2 - 8
h, rt (ref 10). d FeCl3 (0.1 equiv), Hacac (0.31 equiv), DIPEA (4.6 equiv), BzCl
(4.0 equiv), 4 – 8 h, rt (ref 11). e FeCl3 (0.1 equiv), Hbtfa (0.2 equiv), DIPEA
(4.0 equiv), BzCl (3.0 equiv), 3 h, rt (ref 12a).
We then used free methyl glycosides 63, 65, 67, 69 and 71 as
substrates to evaluate this method (Scheme 2). These
substrates firstly reacted with 1.5 equiv of BzCl in the method.
For substrates 65 and 67, 6-OBz-β-glucopyranoside 66 and 3-
OBz-α-galactopyranoside 68 were obtained in moderate yields
(62% and 71%, respectively). For substrates 63, 69 and 71, once
their mono-benzoylated products were formed, these mono-
benzoylated products were further benzoylated to form di-
benzoylated products immediately. Therefore, substrates 63,
69 and 71 were used to react with 2.5 equiv of DIPEA and 2.5
equiv of BzCl. Consequently, di-benzoylated products 64, 70 and
72 were obtained in 78%, 94% and 89% yields respectively. For
iron-based catalysts,10-12a only the di-benzoylation of substrates
containing cis-diol (69, 71) was feasible, which required more
DIPEA and BzCl, and longer reaction time.
We then evaluated the scope of this method with various
acylation reagents. Methyl-4,6-benzylidene-α-D-glucoside 1
containing trans-diol and methyl-6-OTBS-β-D-galactoside 23
containing cis-diol were used to test with various acylation
reagents (Scheme 3), including p-I-BzCl, p-M-BzCl, PivCl, a long-
chain aliphatic carboxylic acid chloride (C15H31COCl) and two
Scheme 4 SnCl2-catalyzed selective acylation in a large-scale
OTBDPS
OTBDPS
O
O
HO
HO
HO
HO
19b
20b
SnCl2 (1.0 mol %)
DIPEA (1.5 equiv)
BzCl (1.5 equiv)
HO
BzO
OMe
OMe
83%
1.0 g
HO OTBS
HO OTBS
O
CH3CN (10 mL)
rt.,1h
O
OMe
23
OMe
24
HO
BzO
HO
HO
93%
580 mg
Mechanism studies.
In this method, SnCl2 showed no or low catalytic activity for
glycosides 3 and 73, containing a trans-diol moiety without an
adjacent axial group, for the glycoside 74, containing a hydroxyl
group adjacent to an axial group, and for the glycoside 75,
containing two spaced hydroxyl groups, one of which is
adjacent to an axial group. This indicated that both the vicinal-
diol moiety and the adjacent axial group played key roles for the
catalytic activity of SnCl2. In order to explore how SnCl2 played
a catalytic role (Scheme 5), we further compared the
benzoylation of mono-hydroxyl substrates 76 and 78 with and
without the catalysis of SnCl2. It was observed that generation
4 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
rates of benzoylated products 77 and 79 were increased with activity is shown since the Sn-O bond is slightly easier to break
the addition of 0.1 equiv of SnCl2, indicating that SnCl2 still than the H-O bond in this case. HoweDveOrI:, 1a0.1h0y3Vd9i/erDwo0xAGrytCilcl0eg2Or7on3lu9inpAe
played a catalytic role in the cases. We then used 76 and its adjancent to this Sn-O species is prone to form a five-
corresponding diol substrate 55 for a competitive reaction. It membered/six-membered ring intermediate with the tin atom
was observed that only the product 56 starting from 55 was in the presence of DIPEA, consequently leading to the more
produced, indicating that an adjacent secondary hydroxyl group easily cleaved Sn-O bond and the much higher benzoylation
assists the catalysis of SnCl2 to the benzoylation of the primary catalytic activity (Figure 2b). Thus, the mechanism for
hydroxyl group of 55. Competitive benzoylations in the benzoylation catalyzed by SnCl2 is analogous to the proposed
presence of the equimolar amounts of 1,2-diol 51 and 1,3-diol mechanism of organotin-mediated protection (Figure 2c).3c In
80 and the equimolar amounts of 51 and 1,4-diol 82 were also the presence of DIPEA, a cyclic dioxolane/dioxane intermediate
evaluated. The ratios of the products 52 and 81, and the C forms between a diol A and a SnCl2 molecule. Then, the
products 52 and 83 were 8.3/1 and 10/1 respectively. The intermediate further reacts with a acylating reagent to form the
results may indicate that the formation of a five-membered/six- intermediate D, where one hydroxyl group is acylated and the
membered ring intermediate between a tin atom and two other one is occupied by the Sn species. The intermediate D
hydroxyl groups is also a source of catalytic activity.
subsequently undergoes ligand exchange with the substrate
diol to regenerate the cyclic intermediate C and the selective
acylated product E. The regioselectivity is controlled by the
steric and stereoelectronic which has been previously
discussed.3c The possible acyl group migration under the basic
condition may decrease the selectivity of acylation.13
Scheme 5 Control experimentsa
OTBS
OTBS
O
O
Ph
O
Ph
O
O
O
O
HO
BzO
O
HO
HO
OMe
73
OMe
3
74
BnO
75
OMe
HO
OH
OMe
HO
HO
OH
SnCl2 shown no or low catalytic activity
a)
DIPEA (1.2 equiv)
BzCl (1.2 equiv)
MeCN, r.t., 2h
DIPEA (1.2 equiv)
BzCl (1.2 equiv)
MeCN, r.t., 2h
OH
OBz
Sn
N
Sn
Sn
OH
OBz
79
HDIPEA
Cl
Sn
ROH
DIPEA
Cl
80
Cl
76
Cl
77
Ph
Ph
Cl
Cl
78
Cl
Cl
Crystaline SnCl2
Cl
°
OR
77
79
Yields with/without 0.1 equiv of SnCl2:
(72/16 %),
(73/30 %)
b)
DIPEA (1.0 equiv)
BzCl (1.0 equiv)
MeCN, r.t., 2h
OBz
77
Cl
OH
OBz
HO
Ph
OH
HO
Ph
Sn
+
+
Cl2SnO
OBz
OBz
+
BzCl
High
Ph
76
56
55
Ph
O
O
C
0.12 mmol
0.12 mmol
1
:
0
reactivity
D
E
OH
51
0.1 mmol
DIPEA (1.0 equiv)
BzCl (1.0 equiv)
MeCN, r.t., 2h
OBz
OH
80
0.1 mmol
OBz
HO
DIPEA
HO
HO
+
:
HO
HO
52
81
8.3
10
1
HO
OSnCl2
HO
OH
HO
SnCl2
DIPEA
BzCl
Low
OH
51
0.1 mmol
OH DIPEA (1.0 equiv)
OBz
OBz
HO
reactivity
HO
HO
+
:
82
+
B
A
BzCl (1.0 equiv)
MeCN, r.t., 2h
83
52
1
0.1 mmol
c)
cis-diol
trans-diol
1,2-diol
1,3-diol
a The yields and ratio were determined by 1H-NMR of crude mixture.
Cl
Cl
O
O
Sn
O
Sn
O
Sn
O
O
O
O
O
O
Sn
In order to explore the interaction between SnCl2, DIPEA and
diol, we added SnCl2, DIPEA and 1,2-diol 55 into acetonitrile in
sequence (Figure S3). It could be observed that, SnCl2 was not
able to be dissolved in acetonitrile (Figure S3a); the aggregated
SnCl2 rapidly dispersed into the solvent with the addition of
DIPEA (Figure S3b), and then changed from white to yellow
(Figure S3c); the formed milky suspension by SnCl2 and DIPEA in
acetonitrile could be stable for a long time at room temperature
(Figure S3d); and this milky suspension became a clear and
transparent solution with the addition of 55 (Figure S3e). This
phenomenon should support the coordination of DIPEA to
SnCl2, and the coordination of 55 to SnCl2 in the presence of
DIPEA. We also explored the interaction between SnCl2, DIPEA
and 1,2-diol 55 (Figure S4) or cis-diol 35 (Figure S5) by 1H NMR
study. SnCl2 could be dissolved into acetonitrile in the presence
of DIPEA and 55 or 35. It was observed that a proton connecting
C-1o of 55 and the proton connecting C-3 of 35 shifted to
upfield, and the other proton connecting C-1o, the proton
connecting C-2o of 55, and the proton connecting C-4 of 35
shifted to downfield slightly with the addition of SnCl2. This
Cl
Cl
C2
C1
C4
C3
Cl
Sn
C
O
O
DIPEA HCl
BzCl
+
E
D
Cl2SnO
OBz
A
DIPEA
+
Figure 2 Proposed catalytic mechanism.
Conclusions
Researchers have been trying to find low- or non-toxic reagents
that can replace organotin reagents in carbohydrate protection
strategies for decades. However, all of these previously
reported reagents are inferior to organotin reagents in one or
more of the aspects, including selectivity, substrate scope,
reaction efficiency and cost. For the first time, we find a low-
toxic reagent for acylation, SnCl2, which is superior or
comparable to organotin reagents in all of these aspects. SnCl2
still showed high catalytic activity when its used amount was as
low as 1 mole%. The substrate scope is as broad as that in
methods using stoichiometric amounts of organotin reagents,
including 1,2-diols, 1,3-diols, glycosides containing cis-diol, and
might support the formation of
a five-membered ring
intermediate between a tin atom and the hydroxyl groups at 1o-
and 2o-positions of 55 or 3- and 4-positions of 35. In light of
these studies, a catalytic mechanism was proposed in Figure 2.
SnCl2 can form Sn-O bond with a hydroxyl group in the presence
of DIPEA (Figure 2a). Only slightly higher benzoylation catalytic
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ARTICLE
Journal Name
Rev., 2018, 118, 11457; (f) Z. Huang and G. DonVgie,wAAcrcti.clCe hOenlmine.
glycosides containing trans-diol. The catalytic activity and
selectivity were proposed to originate from the formation of a
cyclic dioxolane/dioxane-type intermediate between a diol and
Sn species in the presence of DIPEA. The resulting selectivities
are high, and the product pattern can be predicted, which is the
same as that of traditional organotin-mediated approaches.
Usually, the simpler the molecular structure of a reagent, the
cheaper and more readily available the reagent is. Therefore,
among all the reagents previously reported, Taylor’s reagent,
iron-based catalysts, and organotins are more practical due to
their simple molecule structure. The structure of SnCl2 is the
simplest so that SnCl2 is even cheaper than dibutyltin oxide. We
compared these reagents with SnCl2 in table 3. It can be seen,
the acylation using SnCl2 showed the highest reaction efficiency.
Neither Taylor’s reagent nor iron-based catalysts showed
catalytic activity on trans-diol substrates. Thus, SnCl2 as a green
and extremely cheap reagent, should be the best catalyst in
regio/site-selective acylation. However, it has not been found
that SnCl2 exhibited catalytic activity for sulfonylation. Though
SnCl2 exhibits high catalytic activity for acetylation, the resulting
selectivity is relatively poor likely due to acetyl group migration.
Therefore, the use of FeCl3 and Hbtfa should be the best choice
for sulfonylation, while the use of Fe(acac)3 should be the best
choice for acetylation.
Res., 2017, 50, 465.
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3
4
5
Table 3 Comparison of various acylation methods in practicability.
aUsed
amount
a,b Cost
(USD/mol)
Sulfon-
ylation
Trans-
diols
Acyla
-tion
6
7
Catalysts
Taylor’s
reagent
Fe(acac)3
Hacac
Hbtfa
Bu2SnO
(toxic)
5-10%
178-356
Y
N
rt., 4-12h
10%
30%
2-20%
100%
1-10%
1-5%
53
13
13-130
130
1-13
1-5
N
N
Y
Y
Y
N
N
N
Y
Y
Y
rt., 2-8 h
rt., 4-12 h
rt., 1-12 h
c
-
rt., 12 h
rt., 1-2 h
SnCl2
N
b
c
a Relative to substrates (1 mol). The same grade in the same company.
Two steps’ operation.
Conflicts of interest
There are no conflicts to declare.
8
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Acknowledgements
This study was supported by the National Nature Science
Foundation of China (Nos. 21772049, 21272083). The authors
are also grateful to the staffs in the HUST Analytical and Test
Centre for support with the NMR instruments.
9
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DOI: 10.1039/D0GC02739A
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