Stereoselective Synthesis of 1,1′-Disaccharides by Organoboron Catalysis

Article abstract of DOI:10.1002/anie.202004476

The highly stereoselective synthesis of 1,1′-disaccharides was achieved by using 1,2-dihydroxyglycosyl acceptors and glycosyl donors in the presence of a tricyclic borinic acid catalyst. In this reaction, the complexation of the diols and the catalyst is

Full text of DOI:10.1002/anie.202004476

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Accepted Article
Title: Divergent and Stereoselective Synthesis of 1,1′-Disaccharides by
Organoboron Catalysis
Authors: Sanae Izumi, Yusuke Kobayashi, and Yoshiji Takemoto
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Stereoselective Synthesis of 1,1′-Disaccharides by Organoboron
Catalysis
Sanae Izumi, [a] Yusuke Kobayashi, [a] and Yoshiji Takemoto*[a]
Abstract: The highly stereoselective synthesis of 1,1′-disaccharides
was achieved using 1,2-dihydroxyglycosyl acceptors and glycosyl
donors in the presence of a tricyclic borinic acid catalyst. In this
reaction, the complexation of the diols and the catalyst is crucial for
the activation of glycosyl donors, as well as for the 1,2-cis-
configuration of the products. The anomeric stereochemistry of the
glycosyl donor depends on the employed glycosyl donor. Applications
of the produced 1,1′-disaccharides are also described.
glycosyl acceptors in determining the stereochemistry of
glycosylation has been less thoroughly investigated. Thus,
despite the fact that 1,1′-glycosidic bond formation provides the
possibility of controlling the 훼/훽-selectivity of each anomeric
position, only a limited number of catalytic couplings of glycosyl
donors and acceptors bearing appropriately protected hydroxy
groups has been reported to date.
Nonsymmetrical 1,1′-disaccharides are structural motifs in various
biologically active compounds, including bacterial envelope
components and natural products such as succinoyl trehalose
lipids, tunicamycin V, and avilamycin A (Figure 1).[1-5] Due to their
unique structure and biological activity, the derivatization of 1,1′-
disaccharides has received substantial attention. In particular, the
regioselective protection of hydroxy groups in commercially
available 1,1′-훼,훼-trehalose has commonly been employed as a
synthetic strategy for the generation of 1,1′-disaccharides,
although the protection and deprotection procedures usually
result in longwinded synthetic routes.[6]
Figure 1. Selected natural products that contain 1,1′-disaccharides.
Figure 2. Summary of this work.
Compared to the well-established 1,n-O-glycosylation (n ≠ 1′), the
stereoselective synthesis of non-reducing 1,1′-glycosides via
glycosidic bond formation between two anomeric centers is much
more challenging,[7] as the stereochemistry of both anomers must
be controlled simultaneously in order to synthesize the desired
isomer from among the four possible stereoisomers.[2-5]
Furthermore, in contrast to that of glycosyl donors, the role of
So far, several efficient methods to control the stereochemistry of
the anomeric centers of 1,1′-disaccharides have been developed
using cyclic stannanes,[5c,d] mixed acetals,[7d,e] and picolyl-
protected trimethylsilyl ethers[8] as glycosyl acceptors (Figure 2a).
However, there is still room for further exploration of the catalytic
and divergent synthesis of various 1,1′-disaccharides from the
same glycosyl acceptor. In 1994, Yamamoto has proposed the
novel concept of Lewis-acid-assisted Brønsted acid (LBA)
catalysis based on chiral diol·SnCl4 complexes.[9] Recent studies
have also reported stereoselective 1,n-O-glycosylations in which
glycosyl trichloroacetimidates and glycals are activated by in-situ-
generated complexes that are comprised of a Lewis or Brønsted
acid and a glycosyl acceptor (Figure 2b).[10] Moreover, Taylor has
[a]
Sanae Izumi, Dr. Yusuke Kobayashi, Prof. Dr. Yoshiji Takemoto
Graduate School of Pharmaceutical Sciences, Kyoto University
46-29 Shimoadachi-cho, Yoshida, Sakyo-ku, Kyoto 606-8501,
Japan
E-mail: takemoto@pharm.kyoto-u.ac.jp
Supporting information for this article is given via a link at the end
of the document.
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developed a series of mono-functionalizations of various 1,2- and
1,3-diols including acylation, sulfonylation, alkylation, and
arylation reactions using arylboronic acids or diarylborinic acids in
the presence of bases.[11] Diarylborinic acids in particular showed
excellent catalytic performance for the site-selective glycosylation
of polyhydroxy glycosyl acceptors; in these reactions, one of the
alcohols of the glycosyl acceptor is deprotonated by the base to
generate the borate complex.[11d] Based on these reports, we
envisaged that complexation of a diarylborinic acid with a 1,2-
dihydroxyglycosyl acceptor could give a mono-borinate ester. As
the boron center would then coordinate with the remaining
hydroxy group, the acidity of this OH group could be expected to
increase according to LBA theory.[9] In this communication, we
report that in the absence of a base, borinic acid[11] forms a mono-
borinate ester complex with 1,2-dihydroxy (or 1-hydroxy-2-amino)
glycosyl acceptors 1. The 1,1′-glycosylation of appropriate
glycosyl donors, such as glycosyl phosphites 2[12] and
anhydrosugars 4,[13] by 1 proceeds smoothly to give the
corresponding 1,1′-훽,훼- and 1,1′-훼,훼-disaccharides 3 and 5,
respectively, in a cis-fashion relative to the C1 and C2 positions
of the glycosyl acceptors (Figure 2c).
investigated using various glycosyl phosphites and catalyst IV in
dichloromethane at room temperature.
Table 1. Optimization of the reaction conditions for ,-disaccharides.[a]
2A
(x equiv)
Yield
[%]
Entry
Cat.
,/,
‒
1
i (1.2)
i (1.2)
i (1.2)
i (1.2)
i (1.2)
i (1.2)
i (1.2)
i (1.2)
i (1.5)
i (1.5)
i (1.5)
ii (1.5)
iii (1.5)
iv (1.5)
PhB(OH)2
0
2
Ph2BOH
14[b]
29
, only
, only
, only
, only
13.1/1
7.3/1
1.1/1
9.0/1
25.3/1
, only
13.3/1
‒
3
4
5
6
7
8[c]
9
10[e]
11[f]
12
13
14
I
II
III
IV
V
19
80
99
99
15[d]
100
79
63
86[g]
0
We initially investigated the reaction conditions for the synthesis
of 1,1′-,-disaccharide using various organoboron catalysts,[14-
Triflic acid
16]
glycosyl 1,2-diol 1a, and glycosyl donors 2A (i-iv), which are
IV
IV
IV
IV
IV
IV
known to be activated by Brønsted acids (Table 1). Although
glycosyl phosphite 2A (i, pKa of (EtO)2POH = 9.2) was not
activated by phenylboronic acid (entry 1), diphenylborinic acid
slightly promoted the reaction to give the desired ,-adduct 3aA
in 14% yield (entry 2), while the use of the tricyclic borinic acid
catalyst I increased the yield to 29% (entry 3). The regio- and
stereochemistry of 3aA were unambiguously determined as 1,1′-
, based on the 1D and 2D NMR spectra of 3aA.[17] The use of
dimethylated tricyclic catalyst II, which we employed in our
previous work,[15] decreased the yield of 3aA (19%; entry 4). We
then designed tricyclic borinic acid catalyst III, which bears an
electron-withdrawing group on one aromatic ring; the use of
catalyst III improved the yield of 3aA to 80% (entry 5). To our
delight, bis-trifluoromethylated catalyst IV furnished 3aA in almost
quantitative yield (entry 6). Notably, the ,-isomer was obtained
as the major isomer (,/, = 13.1/1), while the introduction of
an additional CF3 group on one of the aromatic rings of catalyst V
decreased the selectivity (entry 7). Furthermore, when a catalytic
amount of the typical Brønsted acid activator triflic acid[12] was
employed, the major product was the glycoside of the 2-OH group
of 1a (33%), while 3aA was obtained in only 15% yield with no
selectivity at the anomeric position (entry 8). These results
suggest that the complexation of diol 1a and the borinic acid
catalyst play an important role in promoting the desired reaction
with high anomeric stereoselectivity. The selectivity could be
improved by changing the solvent to Et2O or MeCN, but this
resulted in decreased chemical yields despite using 1.5 equiv of
the glycosyl donor (entries 10 and 11). The choice of glycosyl
donor was found to be crucial, as glycosyl trichloroacetimidate[18]
(ii, pKa of Cl3CONH2 = 11.2) similarly provided the adduct in good
yield with slightly decreased selectivity (entry 12), whereas
glycosyl acetate (iii, pKa of CH3COOH = 4.7) and glycosyl
phosphate (iv, pKa of (HO)2P(O)OH = 2.2)[19] resulted no reaction
(entries 13 and 14). Therefore, the substrate scope was
‒
0
[a] Isolated yield. [b] The anomeric stereoisomer (,: 9%) was also
isolated. [c] The reaction was performed at ‒78 ºC using 30 mol%
triflic acid. [d] In addition to the other anomeric stereoisomer (,:
25%), the regioisomer (glycoside of the 2-OH group) was also
isolated (33%). For details, see the Supporting Information. [e] Et2O
was used as the solvent instead of CH2Cl2. [f] MeCN was used as the
solvent instead of CH2Cl2. [g] The anomeric stereoisomer (,: 4%)
was also isolated (for details, see the Supporting Information).
To investigate the substrate scope with respect to glycosyl
acceptors, glycosyl phosphite 2A-i was used as the glycosyl
donor (Scheme 1). Glucose with three unprotected -OH groups at
the 1, 2, and 6 positions provided the corresponding adduct 3cA
in 92% yield with perfect ,-selectivity, while the OH group at the
C6 position did not react. In contrast, glucose with four
unprotected -OH groups at the 1, 2, 4, and 6 positions gave the
1,6-diglycosylated adduct 3dAA in 61% yield when treated with
2.4 equiv of 2A-i. These results corroborate the importance of the
complexation of the catalyst with 1,2- and 1,3-diols. Similarly,
3,4,6-tri-O-protected galactose afforded exclusively the ,-
disaccharide 3eA in 86% yield. Using protected mannose and L-
lyxose, ,-disaccharides 3fA and 3gA were obtained as the
major isomers in excellent yield with high selectivity. N-protected
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glucosamine was also applicable to the 1,1′-,-disaccharide
synthesis, whereby the nature of the protecting group is important.
For example, the N-Ac and N-Troc derivatives did not engage in
the reaction, whereas the N-p-Ns- and N-2-NapSO2-protected
glucosamines afforded the corresponding adducts (3lA and 3mA)
in almost quantitative yield. These results imply that the acidity of
the N-H group is crucial for the success of the reaction, possibly
due to its role in the formation of the complex[20] with the borinic
acid catalyst.
combination was expected to be one of the most challenging, as
both the acceptor and donor have lower reactivity compared to
substrates without 2-amino groups.[2,21] After investigating a
variety of combinations of N-protecting groups on the acceptors
and donors,[17] the reaction of N-NapSO2-protected glucosamine
with N-Troc-protected galactosamine in the presence of 10 mol%
of borinic acid catalyst was found to furnish the desired product
(3mG) in 44% yield with perfect anomeric selectivity. We finally
focused on the reaction with lyxose-derived phosphite, as 1,1′-
lyxoside is the core scaffold of natural products such as
avilamycin A.[4] The reaction with glucosyl 1,2-diol furnished
adduct 3aH in 59% yield with good ,-selectivity. The reaction
with mannosyl 1,2-diol proceeded efficiently to afford adduct 3fI
in 94% yield, albeit with moderate selectivity.
[a] The 3-OH group of GluN was glycosylated in 11% yield; for details, see the
Supporting Information.
Scheme 1. Scope with respect to glycosyl acceptors
To broaden the substrate scope of this borinic-acid-catalyzed
reaction, we then investigated the use of various glycosyl
phosphites (Scheme 2). To our delight, the reactions of glucosyl
1,2-diol, galactosyl 1,2-diol, and mannosyl 1,2-diol with galactosyl
phosphite afforded the 1,1′-,-, 1,1′-,-, and 1,1′-,-
disaccharides 3cB, 3eB, and 3fB as single isomers in 84%, 87%,
and 91% yield, respectively. Glycosyl phosphites derived from
glucosamine and galactosamine (GlcN and GalN)[17] also reacted
with 1,2-diol 1a to give the corresponding ,-disaccharides (3aD-
3aF) as the major isomers in good to high yield. We then applied
this methodology to the synthesis of the core 1,1′-trehalosamine
structure of tunicamycin V using glucosamine as the glycosyl
acceptor and galactosamine as the glycosyl donor. This
[a] The 3-OH group of GluN was glycosylated in 26% yield; for details, see the
Supporting Information. [b] The anomeric stereoisomer ,−3aH was also
isolated (7%).
Scheme 2. Scope with respect to glycosyl donors
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We hypothesized that the decreased 1,2-trans-()-selectivity of
3fI (and 3fC) at the anomeric position of the glycosyl donor
originated from the glycosyl phosphites employed, as the
prepared glycosyl phosphites have been found to be mostly -
isomers,[17] and therefore, a significant ratio of 1,2-cis-()-isomer
would be competitively obtained via an SN2-type mechanism.[22]
Thus, we subsequently performed mechanistic studies of this
reaction (Scheme 3). First, the Lewis acidity of catalyst IV was
confirmed to be insufficient for the activation of glycosyl phosphite
2A-i (Scheme 3A). When glycosyl acceptor 1b was treated with
2A-i under the optimized conditions, glycosylation did not occur,
and the substrates were recovered. These results strongly
support our hypothesis that the glycosyl donor is activated by the
‘acidic OH group’ coordinated by the mono-borinate ester of the
glycosyl 1,2-diol.
To clarify the origin of the high anomeric selectivity derived from
the glycosyl phosphites, we carried out time course studies of the
reaction of diol 1a with an -phosphite (-2B) or -phosphite (-
1
2B) using H and 31P NMR spectroscopy in CD2Cl2.[22] When -
2B was employed, the product exhibited almost perfect -
selectivity (Scheme 3B). On the other hand, an / product was
obtained using -2B, whereby the -isomer was still preferentially
produced (Scheme 3C). Isomerization between -2B and -2B
was not observed during the time course study, not even when
0.5 equiv. of (EtO)2POH was added prior to the start of the
reaction (Figure S1). These results indicate that the glycosylation
of the alcohol using glycosyl phosphite proceeds mainly via an
SN2 pathway, in parallel to a minor SN1 pathway, and that the ratio
of the SN1 pathway increases when the -phosphite is used. A
similar 1,2-trans-selective glycosidic bond formation has been
reported in the diarylborinic acid-catalyzed glycosylation due to
the bulkiness of the nucleophiles.11e
We then turned our attention to the divergent synthesis of 1,1′-
disaccharides based on the reaction mechanism that involves the
activation of the glycosyl donor via the ‘activated OH group’ of
glycosyl 1,2-diol 1 by the borinic acid catalyst. We anticipated that
the anhydro sugar 4 could also be activated by the ‘acidic OH
group’ to obtain 1,1′-,-disaccharide (Figure 3).14 After various
reaction parameters, including the catalyst, solvent, and
temperature, were screened,[17] the desired ,-trehalose 5a was
obtained as the major isomer by treating diol 1a with 4 at 0 °C in
acetonitrile in the presence of 20 mol% of catalyst I. The Lewis
acidity of catalyst IV seems to be sufficient to activate donor 4,
albeit that it promoted polymerization; thus, catalyst I was chosen
as the optimal catalyst for the reaction. Under the optimized
conditions, galactosyl 1,2-diol furnished the 1,1′-,-
disaccharides 5b and 5c as the major isomers in good to high
yield.
Figure 3. Synthesis of 1,1′-,-disaccharides.
One of the major advantages of this method is that the free 2-OH
groups of the product can be directly functionalized, whereas fully
protected glycosides sometimes suffer from selective
deprotection and functionalization. To demonstrate the utility of
the products, we carried out the total synthesis of STL-1 using
,-trehalose 5a (Scheme 4). The two free 2-OH groups were
acylated with mono-benzylsuccinic acid 6 to give the diester 7 in
86% yield. Regioselective reductive ring-opening of the
Scheme 3. (A) A control experiment using 1b. (B) Time course studies of the
reaction of diol 1a using 1H and 31P NMR spectroscopy in CD2Cl2 with -
phosphite (-2B) or (C) -phosphite (-2B). ●:,-3aB, ■: ,-3aB, ◆: -2B,
▲: -2B.
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benzylidene acetal of 7[23] and subsequent deprotection of the
TBDPS group afforded 3,4-dihydroxy trehalose 8 in high yield.
The 3,4-dihydroxy groups were then acylated with a fatty acid
using Yamaguchi’s esterification conditions[24] to furnish the
tetraester 9 in 87% yield. Finally, the two benzyl esters and four
benzyl ethers were reductively removed using palladium black
and formic acid to obtain STL-1 in 94% yield. Thus, we
successfully achieved the first total synthesis of a nonsymmetrical
,-trehalose derivative using the catalytic formation of 1,1′-
glycosidic bonds.
In conclusion, we have developed a divergent and stereoselective
synthesis to obtain 1,1′-disaccharides from glycosyl 1,2-diols and
glycosyl donors in the presence of a borinic acid catalyst. The
stereochemistry of the glycosyl 1,2-diol is almost completely
controlled in cis-fashion due to the complexation with the borinic
acid, while the stereochemistry of the other anomer ( or ) is
controlled by the glycosyl donor used. Furthermore, the
complexation of 1,2- and 1,3-diols with borinic acid may generate
an ‘acidic OH group’ that can activate glycosyl donors such as
glycosyl phosphites. This activation mode is fundamentally
different from the previously reported mechanism using an
organoboron catalysts as a Lewis acid. These findings can be
expected to lead to further developments in organoboron
catalysis and glycosylation chemistry; related studies are
currently underway in our laboratory and the results will be
reported in due course.
Keywords: trehalose • carbohydrates • glycosylation •
organocatalysis • total synthesis
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Scheme 4. Application of the adduct ,-5a in the synthesis of STL-1.
Acknowledgements
This work was partly supported by JSPS KAKENHI grant
16H06384. S.I. is grateful for a JSPS Fellowship for Young
Scientists (17J08174).
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COMMUNICATION
M. Nakano, K. Yabiku, M. Shibutani, T. Nakanishi, M. Suenaga, M. Inoue,
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[14] The group of Toshima and Takahashi also greatly contributed to the
development
of
organoboron-catalyzed
functionalizations
of
This article is protected by copyright. All rights reserved.

10.1002/anie.202004476
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
The highly stereoselective synthesis
of 1,1′-disaccharides was achieved
using glycosyl 1,2-diols and glycosyl
donors in the presence of a tricyclic
borinic acid catalyst. While the
complexation between the diol and
the catalyst is crucial for the activation
of the glycosyl donors and the cis
configuration of the product, the
anomeric stereochemistry of the
glycosyl donor depends on the
Sanae Izumi, Yusuke Kobayashi, and
Yoshiji Takemoto*
Page No. – Page No.
Stereoselective Synthesis of 1,1′-
Disaccharides by Organoboron
Catalysis
glycosyl
donor.
In
addition,
applications of the products are
described.
This article is protected by copyright. All rights reserved.