Regio- and Stereoselective Synthesis of 1,2- cis-Glycosides by Anomeric O-Alkylation with Organoboron Catalysis

Article abstract of DOI:10.1021/acs.orglett.8b03823

Regio- and stereoselective synthesis of 1,2-cis-glycosides has been achieved by catalytic anomeric O-alkylation using organoboron compounds. Modulating steric and electronic factors of both catalysts and substrates enables activation of the axially oriented anomeric oxygens of glucose-derived dialkoxyborates. The mild reaction conditions allow broad functional-group tolerance. This approach can be applied to the efficient sequential synthesis of oligosaccharides.

Full text of DOI:10.1021/acs.orglett.8b03823

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Regio- and Stereoselective Synthesis of 1,2-cis-Glycosides by
Anomeric O‑Alkylation with Organoboron Catalysis
Sanae Izumi, Yusuke Kobayashi, and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
S
* Supporting Information
ABSTRACT: Regio- and stereoselective synthesis of 1,2-cis-
glycosides has been achieved by catalytic anomeric O-alkylation
using organoboron compounds. Modulating steric and electronic
factors of both catalysts and substrates enables activation of the
axially oriented anomeric oxygens of glucose-derived dialkox-
yborates. The mild reaction conditions allow broad functional-
group tolerance. This approach can be applied to the efficient
sequential synthesis of oligosaccharides.
Scheme 1. Strategies for Stereoselective Synthesis of
Glycosides
hemical synthesis of oligosaccharides has attracted much
Cattention for medical applications because carbohydrates
are common in natural products and play important roles in
numerous biological processes such as cell−cell communica-
tion, pathogen recognition, and immune response.1 Because of
the structural diversity and complexity of glycoconjugates,
efficient access to a sufficient quantity of pure and structurally
well-defined carbohydrates is crucial to investigate their
biological functions.2 However, complete regio- and stereo-
selective glycosylation is still difficult because transient
oxocarbenium intermediates often cause a severe decrease in
the stereoselectivity of the resulting anomeric isomers.3 To
date, various synthetic strategies to control the anomeric α/β-
configuration have been developed. The neighboring-group
participation of 2-O-acyl groups is a reliable method for trans-
selective glycosylation (Scheme 1a, R2 = Ac).4 In contrast, cis-
selective glycosylation remains challenging,5 and various
strategies for cis-selectivity such as the use of chiral auxiliary
groups at the C-2 position (Scheme 1a, R2 = CHPhCH2SPh),6
O-picoloyl groups,7 and O-(o-tosylamide)benzyl groups8 have
been developed. Whereas a range of substrate-controlled
methods for cis-selective glycosylation including intramolecular
approaches9 and conformational restriction control10 have
been reported, effort has also been devoted to developing new
catalytic systems.11 For example, the regio- and cis-selective
glycosylation of a 1,2-anhydroglycosyl donor has been
achieved using glycosyl-acceptor-derived boronic12 or borinic13
ester catalysts.
apply this protocol to the synthesis of 1,2-cis-α-glucosides.
Furthermore, catalytic anomeric O-alkylation to form oligo-
saccharides has not been achieved to date because of the
requirement of a stoichiometric amount of a strong base15,16 or
organotin reagent.14 Recently, boronic acids or borinic acids
have been used as effective catalysts for not only stereo- or
O-Alkylation of anomeric hydroxy groups, in which
oxocarbenium cations are not formed, is another approach
for stereoselective synthesis of glycosides (Scheme 1b). Based
on the high nucleophilicity of β-oxide anions of hexoses, the
reaction generally provides kinetically controlled products such
as 1,2-trans-β-glucosides.14a,b,15 Therefore, it seems difficult to
Received: November 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03823
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
regioselective protection of 1,2- and 1,3-diols17b−d,18,19 but also
regioselective glycosylation.12,17a,e,f,20 Although the functional-
ization of equatorial OH groups in hexoses has been achieved
with high selectivity, few reports describe the predominant
alkylation of axial OH groups because of their weaker
nucleophilicity than that of equatorial groups.12a Herein, we
report a catalytic anomeric O-alkylation of 1,2-dihydroxyglu-
coses 1 via borate complexes with borinic acids, providing 1,2-
cis-α-glucosides through predominant activation of axially
oriented anomeric oxygens (Scheme 1c).
afforded high regioselectivity (cis-3aa/4aa = 12, entry 9). In all
cases, no trans-product was obtained irrespective of the
organoboron catalyst used (entries 1−9). Optimization of
the base revealed that i-Pr2NEt was the best choice; a less
bulky base like Et3N completely inhibited the reaction because
of its high nucleophilicity toward 2a (entry 10). Stronger bases
such as DBU and Cs2CO3 produced trans-3aa, which led us to
investigate the formation of trans-3aa as a major product
(entries 13−16). Use of Cs2CO3 as the base and 1,2-
dichloroethane as the solvent in the absence of catalyst
completely changed the selectivity, furnishing trans-3aa
exclusively.16h These results clearly demonstrate the impor-
tance of borinic acids in regio- and stereoselective O-alkylation.
Using the optimized reaction conditions, we investigated the
substrate scope of glucose-derived diols 1b−h in the reaction
with triflate 2a (Table 2). Although 6g showed excellent
We initially examined the reaction of diol 1a and triflate 2a
in the presence of 10 mol % of commercially available
phenylboronic acid 5 and 4 Å molecular sieves in MeCN
(Table 1).21 As expected, no 1,2-trans-product was detected,
Table 1. Screening of Reaction Conditions
a
Table 2. Scope of Diol 1
cis-
trans-
a
a
a
3aa
3aa
4aa
cis-3aa/
b
entry cat.
base
(%)
(%)
(%) (trans-3aa + 4aa)
1
2
3
4
5
6
7
8
5
6a
7
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
Et3N
PMP
DTBMP
DBU
Cs2CO3
Cs2CO3
Cs2CO3
21
60
50
18
42
58
82
89
92
2
79
4
10
72
8
0
0
0
0
0
0
0
0
0
0
0
0
11
0.6
23
73
31
32
26
20
21
31
11
9
7
0
17
0
0
0.7
1.9
1.9
0.9
2.0
1.9
7.2
6b
6c
6d
6e
6f
6g
6e
6e
6e
6e
6e
9.7
c
9
12
10
11
12
13
14
15
16
a
e
4.7
Isolated yields.
f
0.9
6.3
0.4
11
0
0
selectivity, we chose 6e to clarify the effect of protecting
groups24 on regioselectivity. The mild catalytic conditions
allowed broad functional-group tolerance, including trityl (1b),
benzoyl (1c), acetal (1e−g), and silyl groups (1g and 1h).
Moreover, the steric hindrance of 6-O-protecting groups
dramatically affected the regioselectivity of the reaction. In
fact, 6-O-trityl diol 1b increased the yield of byproduct 4ba
compared with those obtained using 6-O-benzyl and 6-O-
benzoyl diols 1a and 1c. However, 6-O-unprotected derivative
1d gave the desired cis-3da in 94% yield with complete
regioselectivity, indicating that the reaction does not always
require the protection of OH groups. In contrast, 3-O-
protecting groups should be bulky to achieve high
regioselectivity. Although 3-O-unprotected glucose 1e pro-
vided 2-O-alkylated adduct 4ea as a major adduct rather than
cis-3ea, 1g with a bulky TBDPS group exhibited complete
regioselectivity, leading to cis-3ga in 95% yield. The reaction
was also applicable to mannose-derived diol 1i and galactose-
d
0
a
b
Yields of isolated products. Determined from isolated yields.
c
d
Determined from 1H NMR spectra of acetylated products. 1,2-
e
Dichloroethane, 40 °C, 24 h. PMP: 1,2,2,6,6-pentamethylpiperidine.
f
DTBMP: 2,6-di-tert-butyl-4-methylpyridine.
and the desired product cis-3aa was obtained, albeit in low
yield (21%), together with 2-O-alkylated byproduct 4aa (entry
1). To improve the regioselectivity (cis-3aa/4aa), phenyl-
borinic acid 6a and triarylborane 722 were screened; 6a showed
catalytic performance superior to that of 7 (entries 2 and 3).
Modification of 6a to ortho-substituted 6b23 and para-
substituted 6c and 6d did not improve the selectivity (entries
4−6). Further investigation revealed that tricyclic borinic acid
6e17f gave cis-3aa in 82% yield with high selectivity (cis-3aa/
4aa = 7.2, entry 7). In addition, the electron-rich catalyst 6g
B
DOI: 10.1021/acs.orglett.8b03823
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Letter
derived diol 1j, giving the corresponding products cis-3ia and
cis-3ja. As expected, excellent regioselectivity was observed in
the case of mannose but not in the case of galactose. Further
modification of the C-3 protecting group of 1,2-diol 1j as well
as catalyst 6 would be needed to improve the selectivity in this
case.
configuration. Notably, while catalyst 6e afforded cis-3ag in
only 53% yield, the same reaction with catalyst 6g raised the
yield of cis-3ag to 86%. Except for disaccharide cis-3jg derived
from 1,2-dihydroxygalactose 1j, branched products cis-3ag−aj
and 3ig were obtained as single isomers in good yields.
To clarify the reaction mechanism of the catalytic anomeric
O-alkylation using borinic acids 6, control experiments were
carried out with 2-deoxy and 2-O-protected glucoses 8a−c
under the same conditions (eqs 1 and 2). In each case, no O-
As shown in Table 3, the reaction scope with triflates 2b−j
was further examined with diols 1a, 1i, and 1j. Primary triflates
Table 3. Scope of Triflate 2
alkylation occurred, and the starting materials 8a−c were fully
recovered. These results strongly demonstrated the necessity of
a 1,2-diol moiety to activate the axially oriented anomeric
oxygen.
The mild reaction conditions using organoborinic acids
allowed broad functional-group tolerance, including a free OH
group, which enabled the sequential synthesis of oligosacchar-
ides (Scheme 2a).25 We first explored the transformation of
glycoside cis-3da into α(1,6)-linked oligosaccharide 10. The
triflation of cis-3da was followed by the borinic acid 6g-
catalyzed O-alkylation of 1d to give trisaccharide 9 in 93%
yield. One equivalent of diol 1d was sufficient to complete the
reaction. The iterative exposure of 9 to the two-step sequence
(triflation and O-alkylation) afforded the desired tetrasacchar-
ide 10 as a single isomer. Compared with the previous work in
which deprotection of 6-O-protecting groups is needed to
prepare α(1,6)-linked glucosyl backbones,26 this mild and
straightforward synthetic method represents an efficient
alternative.
We next applied the anomeric O-alkylation to 1,2,4,6-
tetrahydroxyglucose 11 to synthesize β(1,6)- and α(1,6)-linked
trisaccharide 14 (Scheme 2b). The initial differentiation of 1,2-
and 4,6-diol units in 11, which was synthesized from
commercially available 1,2:5,6-di-O-isopropylidene-α-D-gluco-
furanose in two steps,27 was the key to the success of the
anomeric O-alkylation. Although borinic acids are known to
preferentially bind 1,2-diols over 1,3-diols,17d there has been
no report on the site-selective protection of glucose-derived
tetraols. We thus examined the boron-catalyzed O-alkylation of
tetraol 11. The reaction of 11 with borinic acid 6g occurred at
the 1-O-position over the 6-O-position to give the desired
product 12 in 71% yield, whereas borinic acid 6e gave 12 in
59% yield. Moreover, the remaining 4,6-diol moiety of triol 12
can be functionalized regioselectively. Following Taylor’s
procedure, the trans-selective glycosylation17a of triol 12 was
carried out with glycosyl bromide 13 in the presence of the
same borinic acid 6g to provide trisaccharide 14 in good yield,
whereas the chemical yield of 14 decreased markedly without
6g or with phenylborinic acid.
a
b
2 (2.0 equiv), catalyst (20 mol %), 60 °C, 72 h. 2 (2.0 equiv), 6g
c
(20 mol %), rt, 48 h. 2 (2.0 equiv), 6g (20 mol %), 60 °C, 48 h.
2b−f with various kinds of protecting groups provided the
desired products cis-3ab−3af, 3ib, and 3id in good to excellent
yields. Furthermore, not only primary triflates but also
secondary triflates 2g−j successfully underwent the anomeric
O-alkylation with diol 1a in the presence of 20 mol % of
catalyst 6g, resulting in the corresponding α(1,4)- and α(1,3)-
linked products cis-3ag−aj with complete inversion of
Finally, the three-step synthesis of tetrasaccharide 18 bearing
β(1,2)- and α(1,6)-glycosyl bonds was attempted by
combining anomeric O-alkylation and conventional glycosyla-
tion (Scheme 2c). The initial O-alkylation of diol 1g and
C
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anomeric fluoride of product 16 remained intact under the
reaction conditions. The obtained trisaccharide 16 was then
converted into oligosaccharide 18 in 55% yield by treatment
with alcohol 17 in the presence of Cp2HfCl2 and AgClO4.28
The reaction took place in an α-selective manner, isolating the
target molecule as a single product in only three steps.
In conclusion, we have developed a regio- and stereo-
selective synthetic route to 1,2-cis-glycosides by anomeric O-
alkylation using tricyclic borinic acids. The novelty of this
method is activating axially oriented anomeric oxygens
diastereoselectively by modulating steric and electronic factors
of both catalysts and substrates. The mild reaction conditions
provide broad functional-group tolerance and enable efficient
sequential synthesis of oligosaccharides. Studies on the further
scope expansion and synthetic applications of this route are
currently underway in our laboratory.
Scheme 2. Efficient Synthesis of Oligosaccharides
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03823.
Experimental details; methods and results; character-
ization data (PDF)
1H, 13C, and 2D NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: takemoto@pharm.kyoto-u.ac.jp.
ORCID
Yusuke Kobayashi: 0000-0003-3074-7378
Yoshiji Takemoto: 0000-0003-1375-3821
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant No.
16H06384. We gratefully acknowledge the JSPS Research
Fellowship for Young Scientists (S.I., JSPS KAKENHI Grant
No. 17J08174).
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