Full text of DOI:10.1021/acs.orglett.8b01446

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Regioselective One-Pot Benzoylation of Triol and Tetraol Arrays in
Carbohydrates
†
,∥
†,§,∥
‡
†
†
†
†
Tong Li, Tianlu Li,
Tongxiao Cui, Yajing Sun, Fengshan Wang, Hongzhi Cao,
,
,†
Richard R. Schmidt,* and Peng Peng*
†National Glycoengineering Research Center, Shandong Provincial Key Laboratory of Carbohydrate Chemistry and Glycobiology,
School of Pharmaceutical Sciences, Shandong University, Wenhua West Road #44, Jinan, Shandong 250012, China
‡
Department of Chemistry, University of Konstanz, D-78457 Konstanz, Germany
§
Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
*
S Supporting Information
ABSTRACT: Protection of 2,3,4-O-unprotected α-galacto- and α-fucopyrano-
sides with BzCN and DMAP/DIPEA as the base afforded directly and
regioselectively the 3-O-unprotected derivatives. The rationale for these studies
was to take advantage of the eventual cooperativity of the “cyanide effect” and “the
alkoxy group mediated diol effect”. This way, even the totally unprotected α-
galactopyranosides could be regioselectively transformed into the corresponding 2,4,6-O-protected derivatives. The great utility
of these building blocks was demonstrated in efficient trisaccharide syntheses.
he density of functional groups in carbohydrates is not
found in any other class of natural products. Nature uses
developing direct and simple methods for the synthesis of
partially protected carbohydrates, as for instance, the often
required 3-O-unprotected galactopyranosides and related
compounds, is of great importance.
T
this enormous possibility for structural diversity in oligosac-
charide and glycoconjugate synthesis as well as for
carbohydrate modification and molecular recognition. There-
fore, selective access to these functional groups via
regioselective protection or masking of the other functional
Benzoyl cyanide (BzCN) is frequently used for partial
11−14
protection of carbohydrates.
However, the influence of
the released cyanide anion on the regioselectivity of 1,2-cis-diol
systems has remained unnoticed. We found recently that
BzCN in the presence of catalytic amounts of 4-
1
−5
groups is a necessity for chemical synthesis.
As this task
often demands a multistep, time-consuming, and tedious
1
5
endeavor, there are strong incentives to develop efficient one-
(
dimethylamino)pyridine (DMAP) leads to preferential
4
−6
16
pot procedures.
To this end, the distinctness of each of the
axial benzoylation. This “cyanide effect” is based on dual
hydrogen bonding to the axial oxygen. Thus, acidity differences
are generated that can be successfully employed to allow the
kinetically controlled 4-O-benzoylation of 3,4-O-unprotected
galactopyranosides and the structurally related 1,2-cis-diols
present in fuco- and manopyranosides or myo-inositols.
Additionally, we observed that equatorial 1,2-trans-diols vicinal
to an axial alkoxy group, under basic conditions, preferentially
functional groups has to be evaluated in order to take
advantage of eventually only minor differences in their
reactivities or, alternatively, to find clues to change the
reactivity order.
A particularly important carbohydrate is galactopyranose, as
it serves often not only for linear carbohydrate chain extension
but also as a branching point, for instance, via the 3- and the 6-
hydroxy groups. Regioselective protection of the primary 6-
hydroxy group is generally performed with sterically demand-
ing groups, thus permitting via orthogonal protection also
selective access to this group. However, selective access to the
secondary 3-hydroxy group is quite challenging, as this group is
mostly found to be more reactive than the 2- and the 4-
hydroxy groups, though not sufficiently more reactive for
regioselective 3-O-reaction. Therefore, temporary protection of
the 3-hydroxy group, for instance, with the help of organo-
17
O-acylate at the hydroxy group next to the axial alkoxy group,
as this arrangement leads, due to accumulation of lone pair
orbitals, to an increase in the oxygen nucleophilicity. This
“
alkoxy group mediated diol effect” is particularly strong when
the alkoxy group is the anomeric group, as present in α-gluco-
and α- galactopyranosides.
These observations provide a rationale for how 2,3,4-O-
unprotected α-galactopyranosides and structurally related
systems permit a direct transformation into 3-O-unprotected
derivatives. The “cyanide effect” with BzCN as the reagent and
DMAP as the catalyst apparently favors 4-O-benzoylation,
while the “alkoxy group mediated diol effect” with BzCN as the
7
−9
10
tin
or organoboron reagents, is performed. After
protection of the other hydroxy groups, the temporary
protection is removed, thus liberating the 3-hydroxy group.
Obviously, such indirect protection procedures are neither
time nor cost-effective. Additionally, due to the low atom-
economy, such procedures are not so desirable considering the
added-up expense of the disposal of the waste. Hence,
Received: May 8, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01446
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Regioselectivity of the Benzoylation of 2,3,4-O-Unprotected Galactopyranoside 1a
product (%)
entry
BzX (equiv)
BzCN (2.1)
base (equiv)
DMAP (0.1)
solvent
temp (°C)
time (h)
2a
3a
4a
5a
6a
1
2
3
4
5
6
7
8
9
DCM
rt
−78
1
10
<3
7
9
<3
67
5
<3
19
10
5
9
10
11
18
<3
8
26
20
5
10
60
52
42
15
51
31
40
70
69
47
17
10
12
16
15
12
28
9
37
10
17
20
<3
15
14
11
<3
12
10
PPY (0.1)
DBU(0.1)
DABCO(0.1)
DMAP (0.1)
DCM/MeCN (3:1)
DCM/DMF (4:1)
DCM/THF(1:1)
DCM/CHCl (1:3)
7
6
13
3
1
1
0
1
CHCl (1:3)
−60
rt
5
18
3
DMAP (0.1)
DIPEA (2.0)
DCM
1
10
12
13
14
15
−78
10
<3
<3
17
<3
10
10
17
25
59
76
38
<3
8
6
22
54
20
5
6
DCM/CHCl (1:3)
3
DIPEA (2.0)
DMAP (0.1)
DIPEA (2.0)
BzF (2.1)
DCM
−78 to rt
48
19
1
1
6
7
Bz 0 (2.1)
BzCl (2.1)
DCM
DCM
−78 to rt
−78 to rt
<3
<3
21
15
<3
<3
42
44
34
21
2
a
All of the reactions were performed with 30 mg of substrate in 3 mL of solvent (∼0.03 M).
reagent and a base generally favors 2-O-benzoylation. This
way, due to a change of the reactivity order of the
galactopyranoside hydroxy groups, the generally kinetically
and thermodynamically favored 3-O-benzoylation, particularly
in the presence of fluoride and benzoate counterions, should
be disfavored. Thus, under kinetic reaction control the desired
catalyzed reaction (entries 6−10) showed that chloroform
addition to DCM (entry 9) or chloroform alone (entry 10)
improved the regioselective formation of 4a. More polar
solvents and, particularly, DMF had a negative effect on the
regioselectivity (entry 7), which may due to the strong
interference of this solvent with internal hydrogen bonding.
Next, we studied the influence of auxiliary bases (entries 11−
14), as neutralization of some of the acid released could have a
positive effect on the reaction course. Indeed, comparison of
the results with addition of diisopropylethylamine (DIPEA, 2.0
equiv; entry 11) with the results in entry 1 showed an increase
in regioselectivity that could be further improved by lowering
the temperature (entry 12) and by the addition of chloroform
to the DCM solvent (entry 13). DIPEA alone, without DMAP
(entry 14) led to a very different result. With benzoyl fluoride
and chloride and benzoic acid anhydride as acylating agents
(entries 15−17), the 2,3-di-O-benzoylated product 5a was
16
3
-O-unprotected derivative should be accessible.
For our exploratory studies, readily available 6-O-tert-butyl-
diphenylsilyl (TBDPS) protected methyl α-D-galactopyrano-
1
8
side 1a was selected. Reaction of 1a with 2.1 equiv of BzCN
in the presence of DMAP as catalyst (0.1 equiv) at room
temperature (rt) in dichloromethane (DCM) revealed low
selectivity (Table 1, entry 1). However, carrying out this
reaction at −78 °C led to a dramatic change: the rationale for
our studies was confirmed; the 2,4-di-O-benzoyl-protected
derivative 4a was by far the major product (entry 2). TLC
monitoring during the reaction course indicated that the
kinetic reaction control strongly favored 2-O-benzoylation to
16
preferentially obtained, as was previously observed.
2
a and thereafter 4-O-benzoylation furnishing 4a. Competitive
These results indicate that under the conditions of entry 13
the relative benzoylation rates of 1a are 2-O > 3-O ≫ 4-O, of
2a are 4-O ≫ 3-O and of 3a are 2-O > 4-O, as derived from
the appearance of the intermediates and the final products (for
details see the SI). Once intermediate 2a is generated, it is by
far faster transformed into 4a than into 5a. Hence, the alkoxy
group mediated diol effect is stronger than the cyanide effect.
However, both effects cooperatively permit the preferential
one-pot formation of the valuable 3-O-unprotected galactopyr-
anoside 4a.
To demonstrate the scope of this method for regioselective
2,4-di-O-protection, different substrates with varying groups at
C-1 and C-6, repectively, were investigated (Table 2).
Replacing the silyl protecting group in 1a by the tert-
butyldimethylsilyl (TBDMS) group (compound 1b) or
changing the methyl group at the anomeric oxygen to p-
benzoylation of the 3-hydroxy group in 1a, leading to 3a, was
much slower than the 2-O-benzoylation. The 4-O-benzoylated
derivative of 1a was not observed at all. Formation of the 2,3-
di-O-benzoylated byproduct 5a seemed to originate mainly
from 3a. Due to the high reactivity of the 2-hydroxy group, the
3
,4-di-O-benzoyl derivative was not found at all.
Studies to further improve the regioselective formation of 4a
were performed with other catalysts, as for instance, 4-
pyrrolidinopyridine (PPY, entry 3), 1,8-diazabicyclo(5.4.0)
undec-7-ene (DBU, entry 4), and 1,4-diazabicyclo(2.2.2)-
octane (DABCO, entry 5). However, no improvement in the
regioselective formation of 4a was observed. Interestingly, the
DABCO-catalyzed reaction became very slow after generation
of the 2-O-benzoylated product 2a, which is of practical
usefulness. The studies of the solvent influence on the DMAP
B
DOI: 10.1021/acs.orglett.8b01446
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Regioselectivity of the Benzoylation of Triols
and structurally related compounds should permit also
regioselective 2,4,6-O-protection. This way, from readily
available precursors in a one-pot reaction directly the valuable
3
-O-unprotected galactopyranosides should become available.
To our satisfaction, the unprotected α-galactopyranoside 1i
furnished with 3.1 equiv of BzCN, DMAP as catalyst (0.2
equiv), and DIPEA (3.1 equiv) as auxiliary base the desired 3-
O-unprotected derivative in 62% yield (Table 3, entry 1).
Table 3. Regioselectivity of the Benzoylation of 2,3,4,6-O-
Unprotected Galactopyranosides
a
The reactions were performed with 20 mg of substrate, BzCN (3.1
equiv), DMAP (0.2 equiv), and DIPEA (3.1 equiv) in 30 mL of
CHCl from −10 °C to rt over 8 h.
3
Replacement of the methyl group by the allyl group (1j, entry
2) or the Mp group (1k, entry 3) did not affect the
regioselective formation of 4j and 4k, respectively. These
studies confirmed that 2-O-benzoylation is the fastest reaction;
thereafter the 2,4-di-O-benzoylated derivative appears, and,
finally, the 2,4,6-tri-O-benzoyl derivative is the main product.
Benzoyl migration under the reaction conditions was not
observed.
a
Procedure A: The reactions were performed with 30 mg of substrate,
BzCN (2.1 equiv), DMAP (0.1 equiv), and DIPEA (2.1 equiv) in 3
mL of CHCl /CH Cl (3:1) at −78 °C for 10 h. Procedure B: The
reactions were performed with 30 mg of substrate, BzCN (2.1 equiv),
3
2
2
DMAP (0.2 equiv), and DIPEA (2.1 equiv) in 30 mL of CHCl from
3
b
With the 3-O-unprotected galactopyranosides 4a−k in hand,
the convenient and efficient synthesis of branched and chain
extended oligosaccharides could be demonstrated. With 4a as
−
10 °C to rt for 8 h. 72% was obtained in 1 mmol scale reaction; no
improvement was observed with the dropwise addition (30 min) of
BzCN.
19
acceptor and O-benzyl protected thiogalactopyranoside 7 as
20,21
glycosyl donor using the preactivation procedure,
the α-
nitrophenyl (PNP, 1c) or to 4-methoxyphenyl (Mp, 1d) had
no effect on the regioselectivity (formation of compounds 4b−
d, entries 2−4). In addition, replacement of the 6-O-silyl
protection by 6-O-trityl protection led to the same
regioselectivity (entry 5, transformation of 1e into 4e). As
replacement of the bulky 6-O-protection by 6-O-benzoyl
protection (compound 1f) or by 6-O-benzyl protection
(
(
1−3)-linked disaccharide 8 was obtained in good yield
Scheme 1). 6-O-Desilylation with TBAF in the presence of
Scheme 1. Synthesis of Trisaccharide 11
(
compound 1g) led to a solubility decrease, the reactions
with these compounds had to be performed at lower
concentration and at higher temperature (procedure B);
however, the regioselectivities were not affected (entries 6
and 7). Even with fucopyranoside 1h, having hydrogen instead
of a substituted oxy group at C-6, the regioselectivity remained
the same (entry 8). Hence, independent of the size and the
electronic effect of the substituents at C-6 and C-1 high
regioselectivity is obtained.
In our previous studies, we found that under the conditions
of the cyanide effect for 3,4,6-O-unprotected galactopyrano-
sides the O-acylation rates are 4-O > 6-O > 3-O. As for 2,3,4-
O-unprotected α-galactopyranosides, the O-acylation rates are
found to be 2-O > 3-O ≫ 4-O and, once 2-O-benzoylation has
occurred, 4-O-benzoylation is much faster than 3-O-benzoyla-
tion (see above), 2,3,4,6-O-unprotected α-galactopyranosides
acetic acid afforded 6-O-unprotected acceptor 9, which was
glycosylated with glucosamine derived trichloroacetimidate 10
as donor in the presence of TMSOTf as a catalyst which
furnished the β(1−6)-linkage in very good yield. This way, the
branched trisaccharide 11 was obtained from galactose and
glycosyl donors 7 and 10 in only five steps.
16
22
C
DOI: 10.1021/acs.orglett.8b01446
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chain extension in both directions could be demonstrated,
for instance, with compound 4j (Scheme 2). Reaction with
AUTHOR INFORMATION
Corresponding Authors
■
*
E-mail: pengpeng@sdu.edu.cn.
E-mail: richard.schmidt@uni-konstanz.de.
Scheme 2. Synthesis of Trisaccharide 15
*
ORCID
Hongzhi Cao: 0000-0003-4736-3143
Richard R. Schmidt: 0000-0001-6398-9053
Peng Peng: 0000-0003-4625-6610
Author Contributions
∥
T.L. and T.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
glycosyl donor 10 in the presence of TMSOTf as catalyst
afforded the β(1−3)-linked disaccharide 12. Anomeric O-
This work was financially supported by National Natural
Science Foundation of China (21702125) and the Natural
Science Foundation of Shandong Province, China
(ZR2017BB045), and the Young Scholars Program of
Shandong University. Dedicated to Professor Chi-Huey
Wong on the occasion of his 70th birthday.
deallylation with PdCl in DCM/MeOH leading to 13 and
2
then reaction with Cl CCN in the presence of DBU as catalyst
3
afforded disaccharide donor 14. Reaction again with 4j as
acceptor led to trisaccharide 15 in very high yield. Similarly,
from glycosyl donor 7 and acceptor 4j under 4-nitro-
23,24
benzenesulfenyl chloride/silver triflate
promoted condition
REFERENCES
■
the α(1−3)-linked disaccharide 16 was obtained (Scheme 3).
(
1) Wang, C.-C.; Lee, J.-C.; Luo, S.-Y.; Kulkarni, S. S.; Huang, Y.-W.;
Lee, C.-C.; Chang, K.-L.; Hung, S.-C. Nature 2007, 446, 896.
Scheme 3. Synthesis of α-Gal Trisaccharide 20
(2) Franca
6, 8662.
̧ is, A.; Urban, D.; Beau, J.-M. Angew. Chem., Int. Ed. 2007,
4
(
3) Witschi, M. A.; Gervay-Hague, J. Org. Lett. 2010, 12, 4312.
4) Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900.
5) Boltje, T. J.; Buskas, T.; Boons, G.-J. Nat. Chem. 2009, 1, 611.
6) Zulueta, M. M. L.; Janreddy, D.; Hung, S. C. Isr. J. Chem. 2015,
(
(
(
5
(
5, 347.
7) Grindley, T. B. Adv. Carbohydr. Chem. Biochem. 1998, 53, 17.
(8) Xu, H.; Lu, Y.; Zhou, Y.; Ren, B.; Pei, Y.; Dong, H.; Pei, Z. Adv.
Synth. Catal. 2014, 356, 1735.
(
(
9) Muramatsu, W.; Takemoto, Y. J. Org. Chem. 2013, 78, 2336.
10) Lee, D.; Williamson, C. L.; Chan, L.; Taylor, M. S. J. Am. Chem.
Soc. 2012, 134, 8260.
(
(
11) Abbas, S. A.; Haines, A. H. Carbohydr. Res. 1975, 39, 358.
12) Paulsen, H.; Paal, M.; Schultz, M. Tetrahedron Lett. 1983, 24,
1
(
759.
13) Gege, C.; Vogel, J.; Bendas, G.; Rothe, U.; Schmidt, R. R.
Anomeric O-deallylation (leading to 17) and transformation
into the trichloroacetimidate 18 as glycosyl donor gave with
Chem. - Eur. J. 2000, 6, 111.
(14) Jacquinet, J.-C. Carbohydr. Res. 2004, 339, 349.
21
(
15) Ho
̈
fle, G.; Steglich, W.; Vorbruggen, H. Angew. Chem., Int. Ed.
̈
glucosamine derivative 19 as acceptor under TfOH catalysis
the linear trisaccharide 20 that provides access to an important
Engl. 1978, 17, 569.
2
5
(16) Peng, P.; Linseis, M.; Winter, R. F.; Schmidt, R. R. J. Am. Chem.
Soc. 2016, 138, 6002.
cellular epitope.
The cooperation of two effects, the “alkoxy group mediated
diol effect” and the “cyanide effect”, permits the direct and
regioselective one-pot transformation of 6-O-protected and
completely O-unprotected α-galactopyranosides into their 3-O-
unprotected derivatives. Such valuable compounds are now
readily available and will help improve the efficiency of various
oligosaccharide syntheses. This has been demonstrated in
efficient branched and linear trisaccharide syntheses.
(
2
(
3
17) Kumar, A.; Geng, Y.; Schmidt, R. R. Eur. J. Org. Chem. 2012,
012, 6846.
18) Fleet, G. W. J.; Seymour, L. C. Tetrahedron Lett. 1987, 28,
015.
(19) Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.;
Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734.
(20) Huang, X.; Huang, L.; Wang, H.; Ye, X. S. Angew. Chem., Int.
Ed. 2004, 43, 5221.
(
(
21) Peng, P.; Xiong, D.-C.; Ye, X.-S. Carbohydr. Res. 2014, 384, 1.
22) Roehrig, C. H.; Retz, O. A.; Hareng, L.; Hartung, T.; Schmidt,
ASSOCIATED CONTENT
Supporting Information
■
R. R. ChemBioChem 2005, 6, 1805.
23) Crich, D.; Cai, F.; Yang, F. Carbohydr. Res. 2008, 343, 1858.
(24) Peng, P.; Geng, Y.; Gottker-Schnetmann, I.; Schmidt, R. R. Org.
Lett. 2015, 17, 1421.
25) Eto, T.; Ichikawa, Y.; Nishimura, K.; Ando, S.; Yamakawa, T. J.
Biochem. 1968, 64, 205.
*
S
(
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01446.
̈
(
Experimental details and NMR spectra of compounds
4a−k, 8, 9, 11, 12, 14−16, 18, and 20 (PDF)
D
DOI: 10.1021/acs.orglett.8b01446
Org. Lett. XXXX, XXX, XXX−XXX