1,2-trans Glycosylation via Neighboring Group Participation of 2- O-Alkoxymethyl Groups: Application to One-Pot Oligosaccharide Synthesis

Article abstract of DOI:10.1021/acs.orglett.9b00220

The use of 2-O-alkoxymethyl groups as effective stereodirecting substituents for the construction of 1,2-trans glycosidic linkages is reported. The observed stereoselectivity arises from the intramolecular formation of a five-membered cyclic architecture between the 2-O-alkoxymethyl substituent and the oxocarbenium ion, which provides the expected facial selectivity. Furthermore, the observed stereocontrol and the extremely high reactivity of 2-O-alkoxymethyl-protected donors allowed development of a one-pot sequential glycosylation strategy that should become a powerful tool for the assembly of oligosaccharides.

Full text of DOI:10.1021/acs.orglett.9b00220

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
1,2-trans Glycosylation via Neighboring Group Participation of
2‑O‑Alkoxymethyl Groups: Application to One-Pot Oligosaccharide
Synthesis
Milandip Karak,‡ Yohei Joh,‡ Masahiko Suenaga, Tohru Oishi, and Kohei Torikai*
Department of Chemistry, Faculty and Graduate School of Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395,
Japan
S
* Supporting Information
ABSTRACT: The use of 2-O-alkoxymethyl groups as
effective stereodirecting substituents for the construction of
1,2-trans glycosidic linkages is reported. The observed
stereoselectivity arises from the intramolecular formation of
a five-membered cyclic architecture between the 2-O-
alkoxymethyl substituent and the oxocarbenium ion, which
provides the expected facial selectivity. Furthermore, the
observed stereocontrol and the extremely high reactivity of 2-
O-alkoxymethyl-protected donors allowed development of a
one-pot sequential glycosylation strategy that should become a powerful tool for the assembly of oligosaccharides.
The design of this stereoselective glycosylation using
alkoxymethyl-protected donors is illustrated in Scheme 1. We
n carbohydrate chemistry, the stereoselective formation of
Iglycosidic bonds has become one of the most important
fields of research due to their essential functions in diverse
biological processes.1 Despite the availability of numerous
extraordinary strategies for the efficient synthesis of oligo- and
polysaccharides, anomeric stereochemical control during the
construction of glycosidic linkages remains a fundamental
challenge.2 To date, one of the most robust and commonly
used strategies for the stereoselective formation of glycosidic
bonds is neighboring group participation (NGP).3 In general,
an ester-type participating group, typically a 2-O-acyl
functionality, affords a stable cyclic acyloxonium ion that
blocks nucleophilic attacks from the covered face, thus
facilitating the predominant formation of the 1,2-trans-
glycoside.4 During this NGP, 2-O-acyl groups are considered
to stabilize the cationic intermediate, but very mildly, since acyl
protecting groups are electron-withdrawing by nature.
Furthermore, the difficulties associated with the selective
removal of the 2-O-acyl group, especially for targets possessing
other acyl groups, occasionally increase the number of reaction
steps. In contrast, ether-type substituents endow the donor
with a higher reactivity, but the stereocontrol remains difficult
even when solvent effects are fully taken into account. Thus, to
facilitate the glycochemistry, we have decided to pursue new
protecting groups that (i) can be orthogonally used with acyl
groups, (ii) enhance the glycosylation reactivity by the more
powerful stabilization of the cationic intermediate, and (iii)
simultaneously control the stereoselectivity.
Scheme 1. Proposed NGP Using 2-O-Alkoxymethyl
a
Groups
a
LG = leaving group.
hypothesized that alkoxymethyl groups such as methoxymethyl
(MOM), benzyloxymethyl (BOM), and our recently devel-
oped 2-naphthylmethoxymethyl (NAPOM)5 groups could
engage with the C1 anomeric carbon atom via their acetalic
oxygen atoms to form five-membered cyclic intermediates,
which accept the attack of alcohols exclusively from the
uncovered face.
To verify this hypothesis, we initially examined the
glycosylation of phenylthioglucosides 1 and 3 (Scheme 2).
As expected, glycosylation of 2-O-Me thioglucoside 1 by
treatment with ICl and In(OTf)3 afforded a 1:1 anomer
mixture of 2 (51%).6 Under identical conditions, the
glycosylation of 2-O-BOM substrate 3 afforded 4 in a
stereoselective manner and higher yield; i.e., the β-anomer
was obtained exclusively in 75% yield.
Herein, we report a 1,2-trans-selective glycosylation using
alkoxymethyl functionalities as protecting groups that undergo
NGP, as well as its application to natural products and one-pot
oligosaccharide syntheses.
Received: January 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00220
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Comparison of the Stereoselectivity of the
Glycosylation of 2-O-Me- and 2-O-BOM-Substituted
Thioglucosides 1 and 3
Table 1. Substrates Scope for the 2-O-Alkoxymethyl Group
Protected Glycosylation (PG= protecting group)
With the prospect of an alkoxymethyl-driven 1,2-trans
glycosylation in hand, the reaction conditions were optimized.
After considerable experimentation, we found that the use of
NIS/In(OTf)3 at −78 to −30 °C afforded the best yield with
an excellent stereoselectivity (for details, see Table S3). Thus,
we decided to examine the scope of donors and acceptors in
these optimized conditions (Table 1). As shown in entries 1, 3,
and 5, the 2,3-O-BOM-protected phenyl thioglucoside donor 3
can be efficiently and selectively coupled with a variety of
acceptors such as 5, 9, and 12 to afford the corresponding 1,2-
trans glycosides 6, 10, and 13 in 79−81% yield. Likewise, the
2,3-O-MOM-protected donor 7 (entries 2, 4, and 6) afforded
1,2-trans glycosides 8, 11, and 14 in 76−85% yield. It is worth
noting that the β-selectivity is also guaranteed for the reactions
involving secondary alcohols (entries 5 and 6), i.e., acceptor 12
reacted with the 2-O-BOM (3) and 2-O-MOM (7) donors
smoothly to form β-glycosides 13 (81%) and 14 (76%),
respectively. As a different acceptor, the more challenging fully
benzoylated galactose 15 was selected and coupled with donor
3 (entry 7). Even in this case, the glycosylation proceeded
smoothly to give the desired disaccharides 16 in 54% yield
with high 1,2-trans-selectivity (9:1).
As we had obtained good results using 4,6-O-benzylidene-
protected cyclic donors, we next focused on donors possessing
acyclic protecting groups at the 4,6-O-positions. The
glycosylation of fully armed donor7 2-O-BOM-3,4,6-O-benzyl
glucopyranoside 17 with fully armed acceptor 9 resulted in the
highly stereoselective (7:1) formation of 1,2-trans glycosides
18 (69%, entry 8). Moreover, the glycosylation of donor 17
with fully disarmed acceptor 19 was also very promising, i.e.,
1,2-trans glycosides 20 was obtained in a yield and stereo-
selectivity that is similar to those obtained from entry 8 (66%,
8:1; entry 9). Even when rather disarmed donor 2-O-BOM-
3,4,6-O-benzoyl glucopyranoside 21 was used in combination
with acceptor 9, the desired 1,2-trans glycosides 22 were
isolated in good yield (75%; entry 10) with high β-selectivity
(11:1). This established strategy was then successfully applied
to the synthesis of glucopyranoside natural products (entry
11). The coupling of donor 23 with highly reactive alcohols,
e.g., MeOH, EtOH, and 3-phenylpropanol (5), resulted in the
exclusive formation of β-glucosides 24−26 in high yield (76−
83%). Subsequent orthogonal removal of all BOM and benzyl
protecting groups from 24 and 25, in the presence of an acyl
group, afforded β-D-glucopyranoside natural products S12 and
S13 (for more details, see the SI). Next, we expanded the
scope to 2,3,4,6-O-BOM galactopyranoside donor 27 (entry
12). Although a comparatively lower selectivity (β/α = 4:1)
was observed, the reaction still afforded the disaccharides 28 in
good yield (78%). As all these glycosylations lead predom-
inantly to the formation of 1,2-trans glycosides, it should be
B
DOI: 10.1021/acs.orglett.9b00220
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Letter
Table 1. continued
Table 2. Feasibility of the Glycosylation with Different
Leaving Groups
a
All reactions were quenched when complete donor consumption was
b
detected by TLC and HRMS. For the sake of clarity, only the major
c
isomer (β) is shown together with the β/α ratio. Isolated yields after
d
column chromatography. Determined by 1H NMR and COSY
e
analysis of the mixture of β/α isomers. Solvent: hexane/CH2Cl2 = 3/
2 (v/v).
expected that the NGP of alkoxymethyl groups effectively
controls the stereoselectivity.
Having obtained excellent results via the NGP of 2-O-BOM
and -MOM groups, we turned our attention to a 2-O-
NAPOM-protected donor. The NAPOM group is an
alkoxymethyl-type protecting group that can be removed
selectively in the presence of p-methoxybenzyl or benzyl
groups, which should be advantageous for the synthesis of
carbohydrates. However, the reaction using 2-O-NAPOM
donor 29 and the primary alcohol 9 furnished the desired
product 30 only in 43% yield (entry 13), and a five-membered
cyclic acetal 33 (Scheme 3) was obtained in 53% yield as a
byproduct.
a
For the sake of clarity, only the major isomer (β) is shown together
b
with the β/α ratio. PG = protecting group. Isolated yield after
c
Scheme 3. Plausible Pathway for the Formation of the
Acetal by Product 33
column chromatography. Determined by 1H NMR and COSY
d
analysis of the mixture of β/α isomers. The reaction was also
performed with NIS (1.5 equiv) and TfOH (0.3 equiv) in CH2Cl2 at
−20 °C for 3 h (79% yield; β/α = 9:1).
proceeded to afford the glycoside 37 under predominant
formation of β-anomer (8:1) and excellent yield (86%; entry
3). Sato and co-workers have previously reported that the
reaction of MOM ether 36 and donor 19, using NIS and
TfOH in CH2Cl2 at −20 °C, afforded the α-isomer as the
major product (α/β = 15:1, 90%).8 However, in our hands
under the stipulated conditions, these glycosylation experi-
ments always resulted in the formation of disaccharides 37 in a
highly β-selective manner (β/α = 9:1, 79%). Since we carefully
isolated 37β and determined its structure unambiguously by
COSY and NOESY experiments, we confidently report that 2-
O-MOM-protected glucopyranoside donors afford 1,2-trans
glycosides as the major products (for a detailed assignment and
the determination of the absolute configuration, see the SI).
Subsequently, we applied our newly developed method to a
one-pot synthesis of oligosaccharides. Before launching this
project, we noticed that, at low temperature (ca. −40 °C), 2-O-
BOM thioglucosides quite selectively react with acceptors in
the presence of 2-O-benzoyl donors (for details, see the SI); in
other words, our 2-O-alkoxymethylated donors seemed to be
more reactive than the conventionally armed, and even the
superarmed 2-O-acyl, donors reported by Mydock and
Demchenko.7b,9 We envisaged that the sequential one-pot
glycosylation7a,b,10 of thioglucosides might be successful if the
2-O-alkoxymethylated donors are initially coupled with a 1-
phenylthio-2-O-acyl acceptor at low temperature in order to
form a disaccharide intermediate. The latter could then be
treated with a second acceptor at higher temperature for the
second glycosylation of the 2-O-acyl thioglucoside moiety to
proceed. Thus, we started our synthesis with the coupling
between acceptor 38 and donor 3 using the aforementioned
optimized conditions (Scheme 4). After the first glycosylation
had been completed at −40 °C, the reaction temperature was
raised to 0 °C, where the disaccharide intermediate engaged in
the second glycosylation and coupled with acceptors 5, 9, and
The cyclic acetal byproduct is likely formed via an attack of
the nucleophile (R1OH) on the C7 methylene carbon atom
(CH2−R′′; blue ball) of the NAPOM-protected intermediate
(path b), instead of on the desired C1 carbon atom (red ball)
at the anomeric position (path a). The formation of 33
indicated that the C1−O1 bond in the NAPOM intermediate
(C1−O1NAPOM) is stronger than the C7−O1NAPOM bond and
those in the MOM and BOM intermediates. Furthermore, in
silico analyses suggested that the solvent effects may increase
the yield of 30 (for details, see the SI). After considerable
investigations, we found that conducting the reaction in
hexane/CH2Cl2 (3/2, v/v, Table 1, entry 13) increased the
yield of 30 to 63%, while that of byproduct 33 decreased to
27%. Moreover, a substrate with a benzyl group instead of a
NAPOM group at the C3 position (31) afforded the desired
glycoside 32 in 73% yield (entry 14). As this yield was
comparable to those of MOM and BOM substrates, it was
concluded that 2-O-NAPOM-protected donors can be readily
attached to the substrates of this 1,2-trans-selective glyco-
sylation, thanks to the addition of hexane.
For the broader application, we next investigated the use of
2-O-alkoxymethyl-protected donors having different leaving
groups (Table 2). The reaction between the glycosyl fluoride
34 and the acceptor 9 proceeded smoothly to afford the
desired glycoside 10 with absolute β-selectivity and good yield
(64%; entry 1). Similarly, the glycosylation of trichloroaceti-
midate 35 also afforded disaccharide 10 under exclusive
formation of the β-anomer (68%; entry 2). Moreover, the
glycosylation of ethylthio donor 36 with acceptor 19
C
DOI: 10.1021/acs.orglett.9b00220
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Notes
Scheme 4. Sequential One-Pot Synthesis of 1,2-Trans
Oligosaccharides Using the Double-Glycosylation Strategy
The authors declare the following competing financial
interest(s): A patent regarding this work is pending (Kyushu
University, PCT Application No. PCT/JP2017/46800).
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI (Grant Nos.
JP15K21210, JP18K05462) and grants from the Heiwa
Nakajima Foundation (Japan) and the Nakamura Jishiro
Ikueikai Foundation (Japan) to K.T. M.K. thanks Heiwa
Nakajima Foundation (Japan) and Takeda Science Foundation
(Japan) for research fellowships. We are grateful to Mr.
Takaaki Torikai, Ms. Rumiko Torikai, Mr. Motoaki Yamaoka,
Ms. Michie Yamaoka, Ms. Kimiko Komiya, and Dr. Kazuhiro
Matsunaga for their generous personal financial donations.
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in 64−54% yield as single isolable isomers. Despite the use of
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: torikai@chem.kyushu-univ.jp.
ORCID
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Author Contributions
‡M.K. and Y.J. contributed equally.
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