Regioselectivity of glycosylation reactions of galactose acceptors: An experimental and theoretical study

Article abstract of DOI:10.3762/bjoc.15.294

Regioselective glycosylations allow planning simpler strategies for the synthesis of oligosaccharides, and thus reducing the need of using protecting groups. With the idea of gaining further understanding of such regioselectivity, we analyzed the relative

Full text of DOI:10.3762/bjoc.15.294

Regioselectivity of glycosylation reactions of galactose
acceptors: an experimental and theoretical study
Enrique A. Del Vigo, Carlos A. Stortz and Carla Marino*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 2982–2989.
Universidad de Buenos Aires, Facultad de Ciencias Exactas y
Naturales, Consejo Nacional de Investigaciones Científicas y
Técnicas, Centro de Investigaciones en Hidratos de Carbono
(CIHIDECAR), Departamento de Química Orgánica, Pab. 2, Ciudad
Universitaria, 1428 Buenos Aires, Argentina
doi:10.3762/bjoc.15.294
Received: 09 October 2019
Accepted: 06 December 2019
Published: 19 December 2019
Email:
Associate Editor: S. Flitsch
Carla Marino* - cmarino@qo.fcen.uba.ar
© 2019 Del Vigo et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
Fukui indexes; galactopyranosyl acceptors; galactose donors;
molecular modeling; regioselectivity
Abstract
Regioselective glycosylations allow planning simpler strategies for the synthesis of oligosaccharides, and thus reducing the need of
using protecting groups. With the idea of gaining further understanding of such regioselectivity, we analyzed the relative reactivity
of the OH-3 and OH-4 groups of 2,6-diprotected methyl α- and β-galactopyranoside derivatives in glycosylation reactions. The
glycosyl acceptors were efficiently prepared by simple methodologies, and glycosyl donors with different reactivities were
assessed. High regioselectivities were achieved in favor of the 1→3 products due to the equatorial orientation of the OH-3 group. A
molecular modeling approach endorsed this general trend of favoring O-3 substitution, although it showed some failures to explain
subtler factors governing the difference in regioselectivity between some of the acceptors. However, the Galp-(β1→3)-Galp linkage
could be regioselectively installed by using some of the acceptors assayed herein.
Introduction
Given the importance of carbohydrates in living systems, oligo- regioisomers, with two possible anomeric configurations, the
saccharides and other glycoconjugates are needed to carry out chemical synthesis of complex oligosaccharides is difficult and
the corresponding glycobiological studies. The heterogeneity of a rather time-consuming effort [1]. Therefore, a carefully de-
carbohydrates from natural sources makes their isolation diffi- signed plan is necessary before starting the synthesis of the
cult, which results in synthesis being the best alternative to desired target structure. Such a plan must include the choice of
obtain the required amounts of carbohydrate-containing mole- the glycosylation strategy for the formation of each glycosidic
cules. Due to the chemical nature of carbohydrates, with bond, as well as the design of derivatives with temporary
multiple possible linkage positions giving rise to different protecting groups and one free hydroxy unit in order to achieve
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Beilstein J. Org. Chem. 2019, 15, 2982–2989.
glycosylations with respect to the desired regiochemistry. The
synthesis of such building blocks is usually the most time-
consuming process of oligosaccharide synthesis [2,3].
The knowledge and control of glycosylation regioselectivity of
building blocks with more than one free hydroxy group allows
reducing the usage of protecting groups, and thus developing
simpler reaction sequences for the synthesis of oligosaccha-
rides and glycoconjugates. A current alternative is the use of
biocatalysts [4,5], although limited specific enzymes are avail-
able. Regioselectivity responds to multiple steric and electronic
factors present in both the glycosyl donor and acceptor, and
they are characteristic for each particular sugar. Although rela-
tive reactivity values have been established for glycosyl donors,
it has not been possible to do the same for glycosyl acceptors,
whose relative reactivity is still rather poorly understood [6].
Regioselective approaches for the glycosylation of acceptors
with more than one free hydroxy group have been developed,
and in some of the cases they were successfully rationalized
[7-9]. In other cases, the results could not be supported by theo-
retical studies [10,11].
Figure 1: Studied glycosyl acceptors and donors.
Galp (6), prepared by benzoylation of galactose in pyridine [16]
ᴅ-Galactose (ᴅ-Gal) is one of the most abundant sugars in at low temperature (0 ºC) in order to avoid the formation of
nature and a component of oligosaccharides and glycoconju- furanosic forms, which are usually generated from ᴅ-Gal [17].
gates with relevant functions [12]. Following a methodology The β-anomer 7 was obtained by BF3·OEt2-promoted glycosyl-
previously applied to ᴅ-glucosamine acceptors [8] with some ation [18] with a short reaction time, exploiting anchimeric
modifications, in the present study, we evaluated the model of assistance, followed by Zemplén de-O-acylation. On the other
ᴅ-galactose and analyzed the relative reactivity of the OH-3 and hand, for the synthesis of the α-anomer 8, a SnCl4-promoted
OH-4 groups of methyl α- and β-galactose derivatives 1α/β and glycosylation was found to be very effective [19], but with a
2α/β in glycosylation reactions with glycosyl donors 3–5 longer reaction time in order to allow for anomerization to
(Figure 1). We also compared our experimental results with occur (Scheme 1) [20].
those obtained by a molecular modeling approach.
In our hands, treatment of methyl glycosides 7 and 8 with two
Results and Discussion
equivalents of protecting reagents resulted in the formation of a
For this study, ᴅ-Galp derivatives with both their OH-2 and mixture of di- and trisubstituted derivatives, and thus the regio-
OH-6 group blocked were required. The regioselective functio- selectivity could not be controlled. All Galp acceptors were pre-
nalization of carbohydrates is usually a difficult task due to the pared from the corresponding isopropylidene derivatives 9α or
similar reactivity of secondary hydroxy groups [13]. We synthe- 9β. For their preparation, methyl glycosides 7 or 8 were treated
sized derivatives 1α/β and 2α/β in order to compare the differ- with 2,2-dimethoxypropane and catalytic amounts of p-toluene-
ences in the regioselectivity of the glycosylation reaction due to sulfonic acid, followed by a mild treatment with TFA to
the different electron-withdrawing/-donating properties and hydrolyze the formed byproducts, such as open and mixed
anomeric configurations. As donors, 3–5 were chosen to assess acetals [21,22]. Either by benzoylation or benzylation of 9α or
the effects of the donor's reactivity. The use of acetyl groups 9β and subsequent deisopropylidenation, glycosyl acceptors
was avoided, both in the donors and acceptors, to preclude 1α/β and 2α/β were efficiently obtained (Scheme 1). Com-
migration during the glycosylation reactions [14,15].
pounds 1α and 1β were previously prepared, but in lower yield
[23,24], and compound 2α was obtained as a byproduct [25].
Synthesis of the glycosyl acceptors
The glycosyl acceptors 1α/β and 2α/β were prepared employ- Glycosylation reactions
ing protecting group chemistry while trying to simplify the With acceptors 1α/β and 2α/β in hand, we assayed the glycosyl-
reaction sequences and to optimize the yields. Methyl galacto- ation reactions of glycosyl donors 3–5. Trichloroacetimidates 3
pyranosides 7 and 8 were synthesized from per-O-benzoyl-α-ᴅ- [26] and 4 [27] were prepared by treatment of the correspond-
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Beilstein J. Org. Chem. 2019, 15, 2982–2989.
Scheme 1: Synthesis of glycosyl acceptors 1α/β and 2α/β. a) BzCl, pyridine, 0 °C, 2 h; b) BF3·OEt2, MeOH, CH2Cl2, 4 h; c) SnCl4, MeOH, CH2Cl2,
20 h; d) NaOMe/MeOH, CH2Cl2, 0 ºC, 2 h; e) (CH3)2C(OCH3)2, p-TsOH, acetone, rt, 16 h; f) 50% CF3COOH, CH2Cl2, 0 ºC, 15 min; g) BnBr, NaH,
THF, rt, 16 h; h) BzCl, pyridine, CH2Cl2, rt, 12 h; i) AcOH/H2O, 4:1, v/v, 65 ºC, 6 h.
ing benzoylated hemiacetals with trichloroacetonitrile and Galf with a stoichiometric amount of TMSI, and glycosylated in
DBU, as previously described. Glycosylations were performed situ by adding the acceptor in the presence of EtN(iPr)2 as acid
in CH2Cl2 and TMSOTf catalysis (Scheme 2). Galactofura- scavenger (Scheme 3) [28]. The acceptor/donor ratio was 1.4:1
nosyl iodide 5 was obtained by the treatment of per-O-TBS-β-ᴅ- to avoid double glycosylation of the acceptors.
Scheme 2: Glycosylation of D-Galp acceptors 1α/β and 2α/β using trichloroacetimidate donors 3 and 4.
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Beilstein J. Org. Chem. 2019, 15, 2982–2989.
Scheme 3: Glycosylation of acceptors 1α/β using galactofuranosyl iodide 5 as donor.
All glycosylations (Scheme 2 and Scheme 3) were monitored using the same precursors, although the formation of a minor
by TLC, and after the corresponding work-up steps, the amount of the 1→4 regioisomer 13β was not reported [31]. The
crude mixtures were analyzed by 1H NMR spectroscopy observation that 13β was formed (Table 1, entry 4) helped to
to establish the ratio of regioisomeric disaccharides and understand the reaction performance and the relative reactivity
the yield by integration of the signals corresponding to the of hydroxy groups. With the 2,3,4,6-tetra-O-benzyl-β-ᴅ-Galp
anomeric positions or other well-resolved signals. The reaction trichloroacetimidate donor, regioselectivity in favor of the
mixtures were purified by column chromatography in order to OH-3 group of 1α [32] or allyl 2,6-di-O-benzyl-α- or β-ᴅ-Galp
obtain the products for characterization, and to confirm the was also observed [33].
yields of the isolated regioisomers. The structures of the
disaccharides were univocally assigned on the basis For donor 3, there was no major difference between benzylated
of NMR spectra (see Experimental section, Supporting Infor- (1α/β) and benzoylated acceptors (2α/β), and the regioselectivi-
mation File 1). The position of the interglycosidic linkages ty was higher for the α-anomers (compare Table 1, entries 1 and
was verified from the deshielding of the 13C NMR signals 2 or 3 and 4, for example). The low nucleophilic character of
involved in such linkages. For example, for disaccharide 10β the OH-4 group in α-anomers could be associated with the
(1→3-linked), the main product of the coupling between 3 and lower capacity of the O-5 atom to establish hydrogen bond
1β, signals corresponding to C-3 and C-4 were observed interactions due to the anomeric effect [34].
at 80.7 and 68.8 ppm, respectively. Instead, for the minor
product 12β (1→4-linked), such signals were observed at 73.5 For donor 4, the regioselectivity observed for 1α, 1β, and 2α
(C-3) and 76.2 ppm (C-4). A further confirmation was obtained was lower than that observed for 3, but for 2β, the only product
by HMBC analysis, which was particularly useful in the cases detected was the 1→4 disaccharide 15β. On the other hand,
in which only one product was detected. For example, for com- benzoylated acceptors showed higher regioselectivity than
pound 14α, correlations between signals corresponding to H-1' benzylated ones. This fact could be attributed to the with-
and C-3 and between C-1' and H-3 were observed. The stereo- drawing effect of the benzoyl group, which diminished the reac-
chemistry of the newly formed glycosidic linkages was estab- tivity of the proximal OH-4 group with respect to the OH-3
lished from the 3JH-1',H-2' coupling constants, which were moiety [35].
around 8 Hz for disaccharides obtained from pyranosic donor 3
and <0.5 Hz for those obtained from furanosic donors 4 and 5 Comparing the different donors, the regioselectivity observed
[29].
followed the order 3 > 4 > 5 (compare Table 1, entries 1–4 vs
4–8 or 9 and 10), which means that the higher the reactivity of
For all the acceptors, 1→3 glycosylation products were favored the donor was [35,36], the lower the regioselectivity was, as ex-
(Table 1, entries 1–10). This trend is in line with the general pected.
concept that the equatorial position (OH-3) is more reactive
than the axial one (OH-4) due to steric factors [30]. The 1→3 Due to the low stereo- and regioselectivities observed for the
disaccharide 11β was previously obtained in a similar yield glycosylation of donor 5 with benzylated Galp acceptors 1α and
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Table 1: Ratios and yields of 1→3 and 1→4 disaccharides obtained by reaction of donors 3–5 with acceptors 1α/β and 2α/β.
entry
donor
acceptor
product
ratioa
1→3:1→4
yield (%)b
isolatedc
1→3
1→4
NMRa
1
2
3
4
5
6
7
8
9
3
3
3
3
4
4
4
4
5
5
1α
1β
2α
2β
1α
1β
2α
2β
1α
1β
10α
10β
11α
11β
14α
14β
15α
15β
18α
18β
12α
12β
13α
13β
16α
16β
17α
17β
19α
19β
10.3:1
7:1
81
81
90
100
79
95
89
84
56
47
74
78
75
72
74
72
83
83
70
70
10.8:1
5.7:1
3.0:1
1.8:1
7.3:1
1:0
2.8:1d
2.3:1
10
aDetermined from the 1H NMR spectrum of the crude reaction mixture. bCombined yield of the 1→3 and 1→4 regioisomers. cRefers to the isolated
pure products after column chromatography on the basis of the donor amount used in the reaction. d19α was obtained as an inseparable mixture with
20α.
1β (Scheme 2 and Table 1, entries 9 and 10), its glycosylation and Table S1, Supporting Information File 1). After calcula-
reactivity with acceptors 2α/β was not assayed.
tions for each low-energy conformer and Boltzmann-averaging,
the local charges and Fukui functions corresponding to each
compound were generated (Table S2 and Table S3, Supporting
Molecular modeling study
In order to rationalize the observed reactivity of the OH-3/OH-4 Information File 1).
groups of acceptors 1α/β and 2α/β, we decided to pursue molec-
ular modeling experiments to determine the atomic partial The higher reactivity of the O-3 atom with respect to position
charges and condensed-to-atom Fukui functions [37]. The O-4 that was experimentally observed was also predicted by
former parameter can be used as an estimation of the reactivity: modeling. Figure 2 shows the data obtained with the B3LYP
a higher net charge is related to a more facile reaction with a functional for the OH-3 and OH-4 groups, and Table 2 shows
hard electrophile [38]. On the other hand, Fukui functions the difference in the charge of atoms O-3/O-4 (q) and Fukui
describe better soft–soft interactions between nucleophiles and functions (f). These differences are all positive for Fukui func-
electrophiles [8,37,38]. The charge density was calculated for tions, whereas they are negative for charge determinations, indi-
both methods using the Merz–Singh–Kollman scheme (MK) cating that for all acceptors, calculations predict that the OH-3
[39,40]. For the calculation of Fukui functions, besides the moiety is more nucleophilic, having higher negative charges q
known computation of differences in atomic charges between and Fukui coefficients f than the OH-4 function. In the case of
the ground-state molecule and the radical cation (fa) [41], a acylated acceptors (analogs of 2α/β), the system predicted the
direct calculation of the frontier molecular orbitals (fb) [42] was lower selectivity of the β-anomer, using either charges or Fukui
carried out.
coefficients (Table 2). Nevertheless, the change in selectivity
predicted for the benzylated diol analogs of 1α/1β did not match
For simplicity, analogs of acceptors 1α/β and 2α/β, where the experimental trend.
benzoyl and benzyl groups were replaced by acetyl and methyl
moieties, respectively, were used (Figure 2). After a full confor- Similar results were observed with the M06-2X functional
mational search with MM3, the lower-energy structures were (Table 2). The calculations gave a good prediction of the higher
submitted to optimization with B3LYP/6-311+G**, and then, OH-3 group’s reactivity, but an accurate prediction of the trends
single-point calculations with M06-2X/6-311+G** (Figure S1 in selectivity could not be achieved.
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Figure 2: Model Galp 3,4-diol acceptors and data obtained with B3LYP.
Table 2: Differences of charges and Fukui functions of the O-3/O-4 positions for analogs of acceptors 1α/β and 2α/β.
B3LYP calculations
M06-2X calculations
qO-3 − qO-4
faO-3 − faO-4
fbO-3 − fbO-4
qO-3 − qO-4
faO-3 − faO-4
fbO-3 − fbO-4
analog of 1α
analog of 1β
analog of 2α
analog of 2β
−0.029
−0.049
−0.086
−0.070
0.041
0.047
0.030
0.026
0.014
0.037
0.062
0.016
−0.028
−0.047
−0.084
−0.078
0.042
0.039
0.025
0.049
0.035
0.040
0.084
0.030
We have tried to explain the reduced regioselectivity of the have failed to agree with the subtle factors governing the differ-
β-anomers through hydrogen bonding interactions of the OH-3 ences in regioselectivity between some of the acceptors.
and OH-4 groups of the model acceptors. Doutheau and
co-workers proposed that such a reduced regioselectivity could The high regioselectivity achieved for the glycosylation of
be ascribed to the greater basicity of the O-ring of the pyranosyl donor 3 with acceptors 1α and 2α indicates that they
β-anomers [34], which results in a stronger hydrogen bond are good precursors to be taken into account when planning the
OH-4⋅⋅⋅O-5. Although stronger interactions were observed for synthesis of molecules containing the Galp-(β1→3)-Galp motif.
some of the conformers (Table S1, Supporting Information
File 1), they corresponded to the less stable conformers.
Supporting Information
Conclusion
Supporting Information File 1
Simple procedures for the synthesis of acceptors 1α and 2β
were optimized. Experimentally, a greater reactivity of the
OH-3 group was observed for the acceptors 1α/β and 2α/β, in
agreement to what is expected for equatorial hydroxy groups.
Donor 3 reacted with more regioselectivity than 4 and 5, in
accordance with its lower reactivity.
Additional figures and tables, full synthetic details, and 1H
and 13C NMR spectra for compounds 1, 2, and 10–19.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-294-S1.pdf]
Funding
Computational results have set out the predicted increase in re-
activity of the OH-3 moiety compared to that of the OH-4 func-
tion by using either electron density or Fukui functions, but
This work was supported by grants from Universidad de
Buenos Aires (UBA), Agencia Nacional de Promoción
Científica y Tecnológica (ANPCyT), and Consejo Nacional de
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Investigaciones Científicas y Técnicas (CONICET) of
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ORCID® iDs
Carlos A. Stortz - https://orcid.org/0000-0003-4562-3941
Carla Marino - https://orcid.org/0000-0002-0857-4995
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