P- tert-Butyl Groups Improve the Utility of Aromatic Protecting Groups in Carbohydrate Synthesis

Article abstract of DOI:10.1021/acs.orglett.9b01372

Aromatic protective groups are widely used in carbohydrate synthesis owing to their numerous merits. However, they unpredictably make certain compounds insoluble in organic solvents owing to their π-stacking abilities. It was found that introducing a tert

Full text of DOI:10.1021/acs.orglett.9b01372

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
p-tert-Butyl Groups Improve the Utility of Aromatic Protecting
Groups in Carbohydrate Synthesis
Sachi Asano,‡,§ Hide-Nori Tanaka,†,‡ Akihiro Imamura,‡,§ Hideharu Ishida,†,‡,§
and Hiromune Ando*,†,‡
†Center for Highly Advanced Integration of Nano and Life Sciences (G-CHAIN), Gifu University, 1-1 Yanagido, Gifu 501-1193,
Japan
‡The United Graduate School of Agricultural Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
§Department of Applied Bioorganic Chemistry, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
S
* Supporting Information
ABSTRACT: Aromatic protective groups are widely used in carbohydrate synthesis owing to their numerous merits. However,
they unpredictably make certain compounds insoluble in organic solvents owing to their π-stacking abilities. It was found that
introducing a tert-butyl group onto the aryl moiety improves the solubility of highly insoluble carbohydrate derivatives, such as
those of N-acetylglucosamine. In this study, tert-butyl-substituted aromatic protecting groups are demonstrated to work as well
as the original unsubstituted form, while improving the efficiency of glycosylations.
n organic synthesis, protective groups (PGs) serve to
carbohydrate synthesis. Despite these drawbacks, aromatic
Idistinguish intended reaction sites from other comparably PGs are widely employed in carbohydrate synthesis because of
reactive moieties.1 The methods for the introduction and
their otherwise excellent utility.
Benzyl and phenyl ether groups are chemically stable, and
most are selectively removable. Benzylidene acetals are the PGs
of choice for protecting the two hydroxyl groups in 1,3-diols
simultaneously, and they can be removed easily under acidic
conditions. Furthermore, they are convertible into the
corresponding benzoyl esters or benzyl ethers via oxidative
or reductive opening reactions, respectively, to regioselectively
give just one free hydroxyl group.
The benzoyl (Bz) group is the most widely used acyl group
in PGs. This is largely because the moderately bulky phenyl
moiety adjacent to the carbonyl of the Bz group facilitates its
kinetically controlled regioselective installation onto one of
several hydroxyl groups in a sugar compound. More
importantly, the neighboring effects of Bz groups are frequently
exploited for 1,2-trans-selective glycosylations because the
bulkiness of the phenyl moiety suppresses ortho-ester
formation from the acyloxonium cation intermediate. Fur-
thermore, the UV absorptivity of aromatic PGs facilitates
reaction monitoring and product purification.
removal of PGs need to be compatible with other functional
groups in the synthetic unit, and the installed PGs must be
unaffected during the entire process of molecular assembly and
transformation. Therefore, feasible syntheses of highly
functionalized molecules largely depend on the use of well-
chosen PG combinations. PGs for carbohydrate synthesis are
particularly important because the chemical properties of the
PGs used can have profound effects on the reactivities of
glycosylation substrates and the stereoselectivities of glyco-
sylation reactions.2−4
More importantly, PGs are indispensable for converting
hydrophilic saccharides into hydrophobic forms. In practice,
the synthesis of carbohydrates is often complicated by the poor
solubilities of saccharide units in organic solvents, which
hinder transformation reactions and product purification.
Empirically, the installation of fixed aromatic substituents,
such as benzylidene acetals, phenyl (thio)ethers, benzoyl
esters, and phthalimides, can dramatically decrease the
solubilities of saccharides in organic solvents. This is often
due to enhanced π−π (or CH−π) stacking aggregation.
Accordingly, this issue limits the choices of PGs and
glycosylation methods, thereby restricting the scope of
Received: April 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01372
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In this Letter, we present a solution to the aforementioned
solubility issues associated with aromatic protecting groups in
carbohydrate synthesis. Our strategy involves the use of p-tert-
butyl-substituted aromatic PGs, and its utility is demonstrated
through glycan synthesis.
As a means to improve the utility of aromatic PGs, we
envisioned that simply introducing an alkyl substituent at the
aromatic ring of the PG would prevent self-aggregation of
aromatic PG-loaded compounds via π−π or CH−π inter-
actions. We assumed that p-substitution would be most
appropriate, as it would minimize the steric influence of the
alkyl group on the reaction site during the introduction and
removal of the PG.
that the solubility of compound 4c is increased by a factor of
6.9 compared to that of 4a. Particle size measurement also
revealed the distinctly different solubilities of the compounds.
In line with these results, the melting point (mp) of 4c is
significantly lower than those of 4a and 4b, further indicating
that the bulky structure of the p-tert-butyl group disrupts its
crystal packing.8
Given the high solubility of 4c, we next examined the
efficacy of 4c as a glycosyl donor in comparison with 4a
(Scheme 2). Trisaccharide 5 was coupled with each donor in
Scheme 2. Glycosylation of Trisaccharide 5
To evaluate the efficacy of our strategy, we chose the
benzylidene (Bzld)-protected galactosamine (GalN) derivative
4a5 as a poorly soluble standard, which was then compared
with p-n-butyl- and p-tert-butyl-substituted derivatives (4b and
4c, respectively) in terms of solubility in EtOH. To synthesize
4a−4c, GalN derivative 3 underwent 4,6-acetalization with
benzaldehyde dimethylacetal, 2b, and 2c, and introduction of
Troc group at O-3 position (Scheme 1).
a
Scheme 1. Synthesis of GalN Derivatives 4a−4c
CH2Cl2 at −80 °C in the presence of N-iodosuccinimide
(NIS)-TfOH. Despite its poor solubility (soluble in CH2Cl2 at
25 °C but partially precipitated at −80 °C), 4a reacted with 5
to give tetrasaccharide 6a in 85% yield after 1 h. In contrast, 4c
reacted much more rapidly, completing the reaction in 10 min
with a similar glycosidation yield. Thus, 4c serves as a highly
effective glycosyl donor due to its high solubility in the
reaction medium.
a
BDA = benzaldehyde dimethylacetal. CSA = ( )-10-camphorsul-
Next, we investigated the cleavage and transformation of the
p-tert-butyl-substituted benzylidene acetal (Scheme 3) employ-
fonic acid. Troc = 2,2,2-trichloroethoxycarbonyl.
Scheme 3. Manipulation of the TBBzld Group
Solubility in EtOH was determined by following a previously
reported procedure.6 An excess amount of each derivative was
suspended in EtOH (>1 mL) at 40 °C. The suspension was
then cooled to room temperature and filtered to provide a
saturated solution. Solubility (mg/mL) in EtOH was then
obtained from the mass of the residue obtained upon
evaporating 1 mL of the saturated solution.
As shown in Table 1, the solubility of Bzld-protected 4a is
dramatically improved by the introduction of a p-tert-butyl
group. Accordingly, 4c exhibits excellent solubility.
The particle size (diameter) of the solute in EtOH was
measured using dynamic light scattering (DLS).7 This revealed
ing procedures commonly used for benzylidene groups. The
protecting group on 4c was almost quantitatively hydrolyzed in
80% aqueous acetic acid at 60 °C to give its 4,6-diol derivative
7. Regioselective reductive ring opening was also successfully
performed to afford the p-tert-butylbenzyl (TBBn)-protected
Table 1. Solubilities, Particle Sizes, and mps of Bzld-
a
Protected Galactosamine Derivatives in This Study
b
c
compound
solubility (mg/mL) particle size (nm)
mp (°C)
9
derivative. Treatment of 4c with Et3SiH/PhBCl2 afforded 4-
4a (R = H)
4b (R = n-Bu)
4c (R = t-Bu)
22.1
30.8
149.2
199.8
243.3
1.0
189−194
183−188
141−147
O-TBBn derivative 8 in 99%, while 6-O-TBBn isomer 9 was
generated upon treatment with Et3SiH/TfOH.10 These results
indicate that p-tert-butyl substitution of the 4,6-O-benzylidene
group improves the solubilities of the corresponding
carbohydrate derivatives in organic solvents while retaining
the properties of the benzylidene group.
a
b
All data were obtained by single measurement. Solubility in EtOH.
c
5 mg/mL in EtOH. Measured by a Zetasizer Nano ZS (Malvern
Instruments, Ltd., UK).
B
DOI: 10.1021/acs.orglett.9b01372
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Inspired by these results, we examined the efficacy of tert-
butyl substitution for other aromatic PGs such as Bn, Bz, and
phenyl thioether. We used N-acetylglucosamine (GlcNAc) as a
model monosaccharide as it is known for its exceptionally poor
solubility, which is due to its extensive intermolecular
hydrogen bonding and CH−π interactions.11
We used the phenylthioglycoside of 4,6-benzylidenated
GlcNAc (10a), which is insoluble in EtOH, as the benchmark.
Sixteen GlcNAc derivatives (10a−13d) were prepared (Figure
1), and their solubilities, mps, and particle sizes were
group than that of the p-tert-butyl Bn group. Thus, these
results indicate that not only TBBzld groups but also other p-
tert-butyl substituted aromatic PGs are effective for improving
the solubility of carbohydrate derivatives in organic solvents.
The drastic decrease in the particle diameters implies that
supramers12 would be less likely to form in the solutions of
12b and 10d−12d due to the bulkiness of the tert-butyl group.
Further inspired by the potential of the TBBz group, we
employed TBBz groups for the synthesis of the extensively
hydrophobic molecule lactosyl ceramide (LacCer) (Scheme
4). For the construction of the β-glycoside from Glc and Cer,
a
Scheme 4. Glycosylation of a Glc-Cer Acceptor
Figure 1. GlcNAc derivatives used in this study.
a
14a−17a, 19a: R1 = Bz. 14b−17b, 19b: R1 = TBBz. TTBP = 2,4,6-
tri-tert-butylpyrimidine.
TBBz group was utilized in the Glc donor 14b as a neighboring
group to impart β-selectivity. The glycosidation of 14b, which
was promoted by dimethyl(methylthio)sulfonium trifluorome-
thanesulfonate generated in situ,13 produced β-glucosyl
ceramide 16b in a comparable yield to that obtained with
the 2-O-Bz Glc donor without producing the stereoisomer or
the orthoester. Compound 16b was then converted into Glc-
Cer acceptor 17b having two TBBz groups.
As expected, the solubility of 17b is significantly improved
compared with that of the known GlcCer acceptor 17a5
protected with two Bz groups, and thereby 17b undergoes
glycosylation with the galactosyl donor 18 in CH2Cl2 at −40
°C, yielding LacCer derivative 19b in high yield. In contrast,
the low solubility of 17a (soluble in CH2Cl2 at 25 °C but
largely precipitated at −40 °C) depresses the glycosylation
yield at the same temperature.
These results demonstrate that the TBBz group is a
promising alternative to the Bz group widely used in
carbohydrate chemistry, not only for improving the solubility
of glycosylation units but also for directing 1,2-trans-
glycosidation. The high solubility at low temperature endowed
by TBBz groups as well as other tert-butyl-substituted aromatic
PGs may enable solvent effects (e.g., nitrile solvent effect,
ethereal solvent effect) to be exploited during glycosylation
reactions and help to suppress side-reactions during chemical
transformations.
Figure 2. Relationships between mp, solubility, and particle size of
GlcNAc derivatives. The colors of the data points indicate their
particle diameters (∼1.0 nm (red), ∼300 nm (yellow), ∼1000 nm
(green), and N.D. (blue)).
measured. The scatter diagram in Figure 2 indicates the
considerable correlation among these parameters. Again,
TBBzld introduction (10b, 11b, 12b, and 13b) improves the
solubility of the corresponding Bzld-protected derivatives to a
large extent. These results are in contrast to p-nitrophenyl O-
glycoside of GlcNAc.11b While p-tert-butyl-substituted phenyl-
sulfenyl (10c and 11c), Bz (12c), and Bn (13c) groups exert
weak effects, their incorporation in combination with the
TBBzld group was found to be significantly effective.
Comparison between compounds 12c−12d and 13c−13d
revealed the higher efficiency of the p-tert-butyl Bz (TBBz)
C
DOI: 10.1021/acs.orglett.9b01372
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) Sakagami, M.; Hamana, H. Tetrahedron Lett. 2000, 41, 5547−
5551.
In summary, we have found p-tert-butyl substitution of
aromatic PGs effective as a strategy to improve the solubility of
carbohydrate derivatives in organic solvents. This methodology
would be useful for various oligosaccharide syntheses,
especially for impeding the intra- and intermolecular hydro-
phobic interactions of protected oligosaccharides composed of
repeating sugar residues. tert-Butyl-substituted aromatic PG
could be employed as the equivalents of parent aromatic PGs,
which are thus highly compatible with established strategies of
carbohydrate synthesis. The concept described in this Letter
may be extendable to the syntheses of polar or aggregate
compounds.
(10) DeNinno, M. P.; Etienne, J. B.; Duplantier, K. C. Tetrahedron
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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.9b01372.
Additional experimental details and characterization data
1
for all new compounds with their H and 13C spectra
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hando@gifu-u.ac.jp.
ORCID
Hide-Nori Tanaka: 0000-0001-5307-4909
Hiromune Ando: 0000-0002-0551-0830
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by JSPS KAKENHI Grant
Numbers JP18K05461 (to H.-N. T.), JP15K07409 (to H.I.),
JP15H04495 (to H.A.), and JP18H03942 (to H.A.); JST
CREST Grant Number JPMJCR18H2 (to H.A.); and by
Mizutani Foundation for Glycoscience (to H.A.). We thank
Prof. Iwamoto (Gifu Univ.) for technical guidance on the DLS
analysis.
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DOI: 10.1021/acs.orglett.9b01372
Org. Lett. XXXX, XXX, XXX−XXX