Selection of Neighboring Group Participation Intermediates of Fully Acylated Donors around the Glycosylation Sites in Oligosaccharide Acceptors

Article abstract of DOI:10.1021/acs.orglett.9b03601

Stereo- and regioselective formation of glycosidic linkages is a challenging topic in oligosaccharide syntheses. The stereoselective construction of 1,2-trans-glycosides generally involves neighboring group participation, which is less successful when syn

Full text of DOI:10.1021/acs.orglett.9b03601

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Selection of Neighboring Group Participation Intermediates of Fully
Acylated Donors around the Glycosylation Sites in Oligosaccharide
Acceptors
Sang-Hyun Son,†,‡ Youngjoo Byun,*,‡ and Nobuo Sakairi*,†
†Division of Environment Materials Science, Graduate School of Environmental Science, Hokkaido University, Kita-ku, Sapporo
060-0810, Japan
‡College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 30019, Republic of Korea
S
* Supporting Information
ABSTRACT: Stereo- and regioselective formation of glycosidic
linkages is a challenging topic in oligosaccharide syntheses. The
stereoselective construction of 1,2-trans-glycosides generally in-
volves neighboring group participation, which is less successful
when synthesizing β-1,3-linked oligosaccharides. The combined
steric effect of a 2-O-substituent and an aglycon moiety in acceptors
increases the efficiency of glycosylation via neighboring group
participation. This steric effect was reduced by using vicinal polyol
acceptors and was demonstrated in the synthesis of 1,3-linked branched oligosaccharides.
tereo- and regioselective construction of the desired
glycosidic linkages is one of the most important tasks in
observed in the glycosylation with acetylated glucosyl
trichloroacetimidates.13 If these phenomena can be fitted
into the category of double stereodifferentiation, why did the
relatively small acetyl and benzoyl groups in the acceptors
influence the anomeric configuration of the glycosides? Herein,
we clarify the influence of the structures of glycosyl acceptors
on the glycosylation outcome in the synthesis of branched
oligosaccharides.
S
oligosaccharide syntheses.1 Utilizing the anchimeric assistance
(also known as neighboring group participation) of the acyl
group at the 2-O-position of the glycosyl donors is the best
established strategy for preparing 1,2-trans glycosides.2 The
carbonyl functionality at the 2-O-position of the donor is
considered to attack an incipient oxocarbenium ion to give a
1,2-dioxonium ion intermediate, which exclusively leads to the
corresponding 1,2-trans glycosidic compound. However, the
inherent drawbacks of this glycosylation include lack of
stereoselectivity and/or extremely low yield of the desired
glycoside even when using 2-O-acylated donors. As an
explanation of this phenomena, Spijker and van Boeckel
proposed a double stereodifferentiation concept, in which the
unfavorable steric hindrance between the 1,2-dioxonium ion
intermediate and the acceptor degraded the stereochemical
outcome of the obtained glycoside as shown in Figure 1a.3
Similar trends were also observed in subsequent studies on
glucosylation,4 mannosylation,5 and galactosylation.6 In
addition to the 2-O-acyl groups, functional groups at remote
positions, e.g., 6-O-acylated D-glucosyl and 4,6-O-acylated D-
galactosyl donors, contribute to the formation of 1,2-cis
glycosides.7 Although there are controversies around this
hypothesis,8 several research groups have provided evidence
supporting the remote participation by performing trapping
experiments for dioxonium cation intermediates9 and by
computational calculations.10
We first compared the glycosylation of monosaccharide 1
and trisaccharide 2 acceptor with fully benzoylated donor 3
using N-iodosuccinimide (NIS)−TfOH14 as a promoter
(Scheme 1). The reaction of 1 with 3 gave β-linked
disaccharide 5 in 58% yield, which can be explained by the
mechanism involving a “normal” 1,2-dioxonium ion inter-
mediate. On the other hand, acceptor 2 gave an anomeric
mixture (α:β = 42:58) of tetrasaccharide 6 in 41% yield.
However, we found that the corresponding 6-O-benzylated
donor 4 afforded a “normal” β-linked tetrasaccharide 7 as the
sole product in 40% yield. Since the presence of a
nonparticipating group at the 6-position led to the recovery
of stereoselectivity, remote participation of the 6-O-benzoyl
group in fully benzoylated donor 3 might induce the α-face
attack of 2 via an 1,6-dioxonium ion intermediate. These
observations led us to hypothesize that the protected glucose
residue at C-1′ and the 2′-O-benzoyl group (and/or the
glucose residue at C-6′ and the 4′-O-benzoyl group) would act
as bulky substituents, obstructing the approach of the 1,2-
dioxonium ion intermediate rather than the 1,6-intermediate
When investigating the feasibility of using dodecyl thioglyco-
sides as glycosyl donors,11 we observed complete loss of β-
selectivity in the reaction of a fully benzoylated donor and a
partially benzoylated gentiopentaoside acceptor to construct a
β-1,3-linked oligosaccharide.12 A similar phenomenon was also
Received: October 11, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03601
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Results of 1,3-Linked Glycosylations of
Trisaccharide Acceptor 2
a
entry
donor
acceptor
product
yield [%] (α/β)
1
2
3
4
D-Glc 3
D-Gal 8
D-Man 9
L-Fuc 10
2
2
2
2
6
41 (41.7:58.3)
48 (52.4:47.6)
88 (α only)
11
12
13
62 (α only)
a
Anomeric ratio determined by integration of the 1H NMR spectrum
of the crude reaction mixture.
Figure 1. Differences between previous study and current study.
Figure 2. Proposed mechanism for regio- and stereoselectivity
glycosylation.
Scheme 1. Glycosylation at 3-Position of Mono- and
Trisaccharide Acceptor
a
suggesting a dominant contribution of the transannular
participation of the 4-O-benzoyl group oriented in the axial
direction. These results proposed that steric repulsion between
the glycosyl donor and acceptor in the transition state is an
important factor in determining stereoselectivity. However, it is
noted that other factors (e.g., reactivity of the glycosyl donor
and acceptor, long-range group participation, or reaction
conditions) can affect the stability of the transition state and
the outcome of the glycosylation process.
In this study, we mainly focused on reducing steric
hindrance around the glycosylation site to facilitate 1,2-trans
glycosylation. To this end, we chose a chimera-type
trisaccharide acceptor 14 that possesses a 2′,3′,4′-vicinal triol
system, because the absence of protecting groups at the O-2′
and O-4′ positions may reduce the steric hindrance around the
3′-OH group, i.e., the glycosylation site (Figure 2).
Furthermore, the bulky fully pivaloylated D-glucose residues
were expected to inhibit undesired glycosylation at either the
2′- or 4′-position. As expected, the reaction of 14 with donor 3
proceeded smoothly under similar conditions as those with the
NIS−TfOH promoter, furnishing pure β-glucoside 15 in an
excellent yield of 91% (Scheme 2). The regioselectivity of the
a
Reagents and conditions: NIS, TfOH, 4 Å MS, CH2Cl2, −20 °C.
toward the glycosylation site, i.e., the 3′-hydroxyl group
(Figure 1b).
We next examined the behavior of other benzoylated
monosaccharide donors (8−10) in the glycosylation with
acceptor 2. As summarized in Table 1, D-mannosyl donor 9
only gave 1,2-trans glycoside 12 in 88% yield, while D-
galalcosyl donor 8 gave anomeric mixtures of tetrasaccharides
11 in low yield with an α/β ratio of 52.4:47.6. In particular, L-
fucosyl donor 10 afforded only α-glycoside product 13,
1
reaction was confirmed after O-acetylation. The H NMR
spectrum of the resulting diacetate 16 showed significant
downfield shifts for the H-2′ (4.86 ppm) and H-4′ (4.77 ppm)
signals. Furthermore, the newly introduced glycosidic linkage
was confirmed to assign a β-anomeric configuration on the
B
DOI: 10.1021/acs.orglett.9b03601
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Organic Letters
Letter
Scheme 2. Glycosylation of Diol Acceptor 19 and Triol
Acceptor 14
Scheme 3. Regio- and Stereo-specific Bis-glycosylation of a
Chimera-Type Acceptor 22
a
a
a
Reagents and conditions: NIS, TfOH, 4 Å MS, CH2Cl2, −40 °C to
−20 °C.
a
Reagents and conditions: NIS, TfOH, 4 Å MS, CH2Cl2, −20 °C.
1
Figure 3. H−1H COSY NMR spectrum of compound 16.
basis of the coupling constant (J1′′′, 2′′′ = 8.2 Hz) of the
anomeric proton at 4.58 ppm (Figure 3). The 1H NMR
spectrum showed no signal attributable to the α-anomer.
Similar phenomena were also observed for the glycosylation at
the 4′-position of disaccharide acceptors 17 and 19. Thus,
3′,4′-diol 17 was subjected to glycosylation with 3 under the
same reaction conditions, and β-linked trisaccharide 18 was
obtained in 93% yield with excellent regio- and stereo-
selectivity. In contrast, 3′-O-benzoylated acceptor 19 gave the
corresponding trisaccharide 20 in poor yield (32%) with an α/
β ratio of 28/72. These results clearly indicated the practical
utility of vicinal diol or triol acceptors in the synthesis of β-
linked branched oligosaccharides.
1
Figure 4. Expansion of H−13C HMBC NMR spectra (δ 4.5−5.5
ppm) for compound 23.
Encouraged by the excellent results for the preliminary
glycosylation of chimera-type acceptors, we attempted to
synthesize a well-known branched heptaglucoside 23 (Scheme
3). We designed a partially pivaloylated pentaglucoside 22
having two vicinal 2,3,4-triol systems as a glycosyl acceptor.
Treatment of a fully pivaloylated thioglucosyl donor 21 with
22 in the presence of NIS−TfOH led to exclusive glycosylation
at both O-3 positions of 22, without any side reaction at the 2-
C
DOI: 10.1021/acs.orglett.9b03601
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Organic Letters
Letter
(6) Park, T.-K.; Kim, I.-J.; Hu, S.-H.; Bilodeau, M. T.; Randolph, J.
T.; Kwon, O.; Danishefsky, S. J. J. Am. Chem. Soc. 1996, 118, 11488−
11500.
(7) (a) Ishikawa, T.; Fletcher, H. G. J. J. Org. Chem. 1969, 34, 563−
571. (b) Frechet, J. M.; Schuerch, C. J. J. Am. Chem. Soc. 1972, 94,
604−609. (c) Demchenko, A. V.; Rousson, E.; Boons, G. − J
Tetrahedron Lett. 1999, 40, 6523−6526.
(8) Kim, K.-S.; Suk, D.-H. Trends Glycosci. Glycotechnol. 2011, 23,
53−66.
(9) (a) Ustyuzhanina, N.; Komarova, B.; Zlotina, N.; Krylov, V.;
Gerbst, A.; Tsvetkov, Y.; Nifantiev, N. Synlett 2006, 2006, 921−923.
(b) Baek, J. Y.; Lee, B.-Y.; Jo, M. G.; Kim, K. S. J. J. Am. Chem. Soc.
2009, 131, 17705−17713.
OH and 4-OH positions. Heptaglucoside 23 was produced in
an isolated yield of 77%, and its complete β-selectivity was
confirmed by NMR spectroscopy. The H NMR spectrum
1
(Figure 4) showed two anomeric protons of the two branched
D-glucose residues at 5.09 ppm, with a large coupling constant
(8.2 Hz). Furthermore, the HMBC NMR spectrum of 23
showed two cross peaks between the anomeric H-1B of the two
branched D-glucose units (5.09 ppm) and C-3 of the two
backbone D-glucose units (86.6 ppm), confirming that the
glycosylation occurred at the two 3-OH groups of 22.
In conclusion, we found that the combined steric effect of a
2-O-substituent and an aglycon moiety in the D-glucopyranose
residues of glycosyl acceptors played a significant role in yield
and stereoselectivity of glycosylation via neighboring group
participation. The steric hindrance could be reduced by
employing vicinal diol or triol acceptors, as was demonstrated
in the synthesis of several branched oligosaccharides including
the phytoalexin elicitor heptaglucoside, with excellent regio-
and stereoselectivity. These findings would provide insights
into the regio- and stereoselective glycosylation of polyol
acceptors, which can be extended to the synthesis of various
complex oligosaccharides.15
(10) Crich, D.; Hu, T.; Cai, F. J. J. Org. Chem. 2008, 73, 8942−8953.
(11) (a) Matsui, H.; Furukawa, J.; Awano, T.; Nishi, N.; Sakairi, N.
Chem. Lett. 2000, 29, 326−327. (b) Son, S.-H.; Tano, C.; Furuike, T.;
Sakairi, N. Carbohydr. Res. 2009, 344, 285−290.
(12) Son, S.-H.; Tano, C.; Furukawa, J.; Furuike, T.; Sakairi, N. Org.
Biomol. Chem. 2008, 6, 1441−1449.
(13) (a) Zeng, Y.; Ning, J.; Kong, F. Tetrahedron Lett. 2002, 43,
3729−3733. (b) Zeng, Y.; Ning, J.; Kong, F. Carbohydr. Res. 2003,
338, 307−311.
(14) Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J. H.
Tetrahedron Lett. 1990, 31, 1331−1334.
(15) (a) Ellervik, U.; Magnusson, G. J. J. Org. Chem. 1998, 63,
́
́
9314−9322. (b) Lopez, J. C.; Agocs, A.; Uriel, C.; Gomez, A. M.;
Fraser-Reid, B. Chem. Commun. 2005, 5088−5090. (c) Zhang, Y.;
Fechter, E. J.; Wang, T.-S. A.; Barrett, D.; Walker, S.; Kahne, D. E. J.
Am. Chem. Soc. 2007, 129, 3080−3081.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03601.
Detailed experimental procedures, characterization, and
1H and 13C spectra of new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: yjbyun1@korea.ac.kr (Y.B.).
*E-mail: nsaka@ees.hokudai.ac.jp (N.S.).
ORCID
Sang-Hyun Son: 0000-0002-8624-078X
Youngjoo Byun: 0000-0002-0297-7734
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially published in a Ph.D. thesis by S.-H.S.
(Hokkaido University, September, 2008). This research was
supported by a grant from Korea University.
REFERENCES
■
(1) (a) Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48,
1900−1934. (b) Smoot, J. T.; Demchenko, A. V. Adv. Carbohydr.
Chem. Biochem. 2009, 62, 161−250. (c) Kaeothip, S.; Demchenko, A.
V. Carbohydr. Res. 2011, 346, 1371−1388.
(2) (a) Capon, B. Chem. Rev. 1969, 69, 407−498. (b) Mydock, L.
K.; Demchenko, A. V. Org. Biomol. Chem. 2010, 8, 497−510.
(3) Spijker, N. M.; van Boeckel, C. A. A. Angew. Chem., Int. Ed. Engl.
1991, 30, 180−183.
(4) Sylla, B.; Descroix, K.; Pain, C.; Gervaise, C.; Jamois, F.; Yvin, J.-
̀
C.; Legentil, L.; Nugier-Chauvin, C.; Daniellou, R.; Ferrieres, V.
Carbohydr. Res. 2010, 345, 1366−1370.
(5) Teumelsan, N.; Huang, X. J. J. Org. Chem. 2007, 72, 8976−8979.
D
DOI: 10.1021/acs.orglett.9b03601
Org. Lett. XXXX, XXX, XXX−XXX