Acid-Catalyzed O-Glycosylation with Stable Thioglycoside Donors

Article abstract of DOI:10.1021/acs.orglett.8b02125

Two classes of thioglycoside, 4-(4-methoxyphenyl)-3-butenylthioglycosides (MBTGs) and 4-(4-methoxyphenyl)-4-pentenylthioglycosides (MPTGs), undergo acid-catalyzed O-glycosylations with a range of sugar and nonsugar alcohols at 25 °C. Electron density at t

Full text of DOI:10.1021/acs.orglett.8b02125

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Acid-Catalyzed O‑Glycosylation with Stable Thioglycoside Donors
Kristina D. Lacey, Rashanique D. Quarels, Shaofu Du, Ashley Fulton, Nicholas J. Reid, Austin Firesheets,
and Justin R. Ragains*
Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, United States
S
* Supporting Information
ABSTRACT: Two classes of thioglycoside, 4-(4-methoxyphenyl)-
3-butenylthioglycosides (MBTGs) and 4-(4-methoxyphenyl)-4-
pentenylthioglycosides (MPTGs), undergo acid-catalyzed O-glyco-
sylations with a range of sugar and nonsugar alcohols at 25 °C.
Electron density at the styrene alkene is critical for reactivity while
sugar protecting group patterns have a minimal effect. In contrast
with most methods for thioglycoside activation, acid-catalyzed
activation of MBTGs is compatible with electroneutral alkenes.
he microheterogeneity of oligosaccharides frequently
synthesis and application of these labile species. Even the
Tprevents their isolation as pure substances from natural related N-phenyltrifluoroacetimidates (PTFAIs, not pictured),
sources.1 Accordingly, chemists often have to turn to
which are often cited as a more stable alternative to TCAIs,
have been bemoaned for their short shelf life.4d Like TCAIs,
thioglycosides are synthesized easily. In contrast to TCAIs,
thioglycosides are prized for their stability toward a host of
conditions (strongly acidic, basic, and nucleophilic) which
make them ideal for multistep synthesis. Nevertheless,
activation of thioglycosides toward O-glycosylation generally
requires highly electrophilic thiophiles that necessitate low
temperatures for activation and have poor compatibility toward
alkenes.4c,e−g While advances have been made recently in the
development of mild and/or alkene-compatible reagents for
thioglycoside activation,5 we wondered if the counterintuitive
development of a glycosyl donor with the stability of a
thioglycoside, but which could be activated using catalytic
acids in the manner of TCAIs, could be enacted.
Recently, we introduced 4-(4-methoxyphenyl)-3-butenyl-
thioglycosides (MBTGs, 1, Scheme 1) as glycosyl donors in a
visible-light-promoted O-glycosylation.6 Blue LED irradiation
of 1, Umemoto’s reagent, and an alcohol resulted in the
formation of glycosidic linkages. We proposed a mechanism
involving the intermediacy of an electron-donor−acceptor
complex 2 and glycosylsulfonium ion 3. Subsequently, we
wondered if protonation of 1 to 6 using catalytic quantities of a
strong acid could result in the formation of a 3-like
intermediate 7 (Scheme 1). Attack of an alcohol on 7 (or
the corresponding oxocarbenium ion) would result in O-
glycosides 4 with regeneration of the proton. Such an approach
would be similar to the activation of pentenyl glycosides
pioneered by Fraser-Reid.7 However, our approach would
require a catalytic acid instead of a stoichiometric electrophile
and the reactivity of glycosylsulfonium ion intermediates8
(instead of e.g. glycosyl bromides) would be exploited. We
have demonstrated that 1 can be stored in a 4 °C refrigerator
enzymatic2,3 and chemical4 syntheses to generate serviceable
quantities of pure material to discover function. Therefore, the
most important step in the multistep synthesis of oligosac-
charides is arguably O-glycosylation.
Two classes of glycosyl donor, glycosyl trichloroacetimidates
(TCAIs)4a,b and thioglycosides4c,e−g (Scheme 1), have
emerged as workhorses for O-glycosylation. TCAIs are marked
by straightforward synthesis from lactols and are activated
toward O-glycosylation under even mildly acidic conditions.
Nevertheless, TCAIs cannot be carried easily through
multistep synthesis. Due to TCAI instability in certain systems,
it is wise to allow a minimal period of time between the
Scheme 1. Glycosyl Trichloroacetimidates, Thioglycosides,
and 4-(4-Methoxyphenyl)-3-butenylthioglycosides
Received: July 6, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02125
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Organic Letters
Letter
for months and that the 4-aryl-3-butenylthioglycoside moiety is
stable toward strongly basic and nucleophilic conditions, just as
one could expect with other alkyl- and arylthioglycosides.6
However, the question of the stability of 1 toward various acids
had not been answered with our initial studies.
HOTf (entry 3) while employment of camphorsulfonic acid
(CSA, entry 4) resulted in no observed consumption of 9a
even after stirring for 24 h at 25 °C. Acid-washed molecular
sieves (AWMS)10 were also inadequate for activation alone
(entry 5) and provided no improvement in yield in
conjunction with HOTf (entry 6). As such, MBTGs are stable
to mildly acidic conditions that activate TCAIs.4a,b,10
Concentration studies (entries 2, 7−9) demonstrated that
0.15 mmol of 9a and 0.075 mmol of 10 in 1 mL of
dichloromethane produced the best results with regard to
reaction rate. Nevertheless, 0.150 mmol of 9a and 0.137 mmol
10 in 1 mL of dichloromethane provided an 89% yield of 11
with an extended reaction time of 4 h (entry 9). A 2 equiv
amount of donor is not necessary for high yields.
We also conducted studies at low temperature (entry 10).
Stirring for 5 h at −20 °C resulted in no observed
consumption of 9a. However, warming the same reaction
mixture to 0 °C and stirring for 3 h resulted in a 70% yield of
11 (entry 10). We were intrigued by the low reactivity at −20
°C, and this observation suggested strategies for orthogonal
syntheses employing temperature control (vide infra). The
alternative solvent mixture of 1:1 Et2O/CH2Cl2 (entry 11) and
acetonitrile (entry 12) provided decreases in yield while
toluene (entry 13) provided a comparable yield to dichloro-
methane. Further, we demonstrated that donors 9b and 9c
were unreactive under the entry 2 conditions, likely due to the
lack of an electron-donating group on benzene (entries 14,
15). Due to short reaction times and high yields, we elected to
employ the entry 2 conditions (Table 1) for further study.
Finally, reaction of 1 mmol of 9a with 1 mmol of alcohol 10
resulted in a 73% yield of 11 after stirring for 3 h at 25 °C,
demonstrating the scalability of this reaction (see Supporting
Information (SI) for details).
Herein, we demonstrate that MBTGs are stable toward
mildly acidic conditions, but have a reactivity profile similar to
TCAIs wherein HOTf and TMSOTf can be utilized for their
activation. High yields of O-glycosidic products can be
obtained at 25 °C and in the presence of electroneutral
alkenes. Further, we demonstrate that the remote activation9
features of this chemistry circumvent the deactivation
problems encountered with tetra-acylated MBTG donors in
our original photochemical approach.6 In addition, we
demonstrate a potential latent-active strategy4g,9 utilizing
cross-metathesis. Further, we demonstrate that 1 is orthogonal
to TCAIs in an O-glycosylation reaction, provided that
adequate temperature control is exercised. Finally, we
introduce a new class of thioglycoside donor (4-(4-methoxy-
phenyl)-4-pentenylthioglycoside, MPTG) and demonstrate the
utility in synthesizing hindered O-glycosides.
In our initial studies (Table 1), we employed tetrabenzyl-
protected MBTG 9a6 with acceptor 10 in dichloromethane.
a
Table 1. Initial Optimization
b
entry
acid
mol % (x) acid time (h) yield (%)
α/β
1 (9a)
2 (9a)
3 (9a)
4 (9a)
TfOH
TfOH
TMSOTf
CSA
100
10
10
10
n.a.
10
10
10
10
10
10
10
10
10
10
0.5
1
1
24
1
2
1
1
4
8
24
2
1
24
24
68
87
85
0
1.5:1
1.4:1
1.4:1
n.a.
n.a.
1.5:1
1:1
1.3:1
1.6:1
1:1.1
2:1
2:3
3:1
Substrate scope studies (Scheme 2) commenced with donor
9a. We demonstrated that glycosylation could proceed in high
yield with a 2° carbohydrate alcohol (entry 1). Further,
moderate to high yields of O-glycosylation products containing
electroneutral alkenes could be obtained with 5-hexen-1-ol
(entry 2) and cholesterol (entry 3). We observed no
conversion of acceptor-linked alkene. In contrast, our photo-
chemical approach resulted in low yields of the desired
products in entries 2/3 along with consumption of the
acceptor-linked alkene.6 These results are particularly signifi-
cant, as alkene-compatible thioglycoside activation is elusi-
ve.5a,b Then, we demonstrated the efficacy of galactosyl donor
9d (entry 4).
c
5 (9a)
n.a.
0
c
6 (9a)
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
75
50
65
89
70
27
51
88
0
d
7
(9a)
e
8 (9a)
e
9 (9a)
f
10 (9a)
11 (9a)
12 (9a)
13 (9a)
g
h
i
Next, we examined tetraacetyl donor 9e6 for glycosylation of
10 (entry 5). Replacement of four benzyl groups with four
acetyl groups results in an ∼1000-fold decrease in reactivity
toward conventional thioglycoside activation due to electron-
withdrawing effects.11 In our previous photochemical studies,
we had determined that 9e was unreactive toward O-
glycosylation, suggesting that the electron density at sulfur
played a role in the reaction. In contrast, 9e was consumed
after 4 h in the presence of 10 mol % HOTf. As expected, this
suggested a styrene protonation event (that is independent of
the electronics of the sugar moiety) followed by fast cyclization
to generate sulfonium ions such as 7 (Scheme 1). Despite this
encouraging result, the reaction generated a disappointing 25%
yield of O-glycoside 16 along with 37% of the product of
acetylation of the alcohol. Results such as this are common
with acetyl protecting groups and are a consequence of the
attack of alcohol onto dioxolenium ions resulting from
14 (9b)
15 (9c)
n.a.
n.a.
0
a
Unless otherwise stated, 0.15 mmol of 9a and 0.075 mmol of 10
were used along with acid and 1 mL of CH2Cl2 and stirred at 25 °C
for the indicated time. Products were purified with silica gel
b
c
d
chromatography. Isolated yields. Added 150 mg of AWMS. Used
e
f
0.0827 mmol of 9a. Used 0.137 mmol of 10. Stirred at −20 °C for 5
g
h
h and then at 0 °C for 3 h. 1:1 Et2O/CH2Cl2 solvent. CH3CN
i
solvent. Toluene solvent.
With 1 equiv of trifluoromethanesulfonic acid (HOTf, entry
1), we obtained a 68% yield of 11 after stirring for 30 min at 25
°C. In contrast, this same reaction required 24 h of irradiation
with blue LEDs using our photochemical approach.6
Decreasing the HOTf loading to 10 mol % led to 87% of 11
with an increase in reaction time (entry 2). Next, we
determined that TMSOTf is an adequate replacement for
B
DOI: 10.1021/acs.orglett.8b02125
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Organic Letters
Letter
a
Scheme 2. Substrate Scope
Scheme 3. Additional Transformations with MBTGs (PMP
= 4-Methoxyphenyl)
a
Unless otherwise stated, 0.15 mmol of MBTG donor and 0.075
mmol of alcohol were used along with 10 mol % HOTf and 1 mL of
CH2Cl2 and stirred at 25 °C until the alcohol had been consumed
(TLC). 20 mol % of Et3N was then added. After evaporation,
products were purified with silica gel chromatography and yields of
which is an effective donor, as shown in Scheme 2.
Glycosylation of 3-butenylthioglycoside alcohol acceptors
with MBTG donors followed by cross metathesis of the
butenyl side chain to generate a new MBTG side chain will be
the subject of future iterative approaches to oligosaccharide
synthesis.
b
isolated products were determined. 37% of the product of alcohol
acetylation was also isolated. Used 0.15 mmol of alcohol.
c
neighboring group participation of 2-position acetyl.12 As an
alternative, we turned to tetrabenzoyl donor 9f and obtained
modest yields of product 17 (entry 6) and respectable yields of
18, also demonstrating orthogonality to alkylthioglycosides
(entry 7). The modest yields in entry 6 are a consequence of
the difficult purification of product 17 due to coeluting
impurities. Similarly difficult purifications were incurred with
the reaction of 9f with acceptor 10 leading to modest yields of
the glycosidic product (46%, data not shown). A potential
solution to these problems is presented with MPTG donor 28
(vide infra).
We previously demonstrated the compatibility of the MBTG
side chain to methanolysis (NaOMe, MeOH), Williamson
etherification (NaH, BnBr), and 10 mol % CSA in CH2Cl2.
However, we were interested in probing the lability of the
MBTG side chain in other common transformations. Thus, we
demonstrated that installation of the benzylidene acetal (9-OH
→ 9-CHPh, Scheme 3) proceeded in high yield with catalytic
Cu(OTf)2 and sonication in CH3CN.13 Benzylation of 9-
CHPh followed by the removal of benzylidene (TFA, MeOH)
afforded 9-OH/Bn, which further demonstrated the stability of
MBTGs toward mild acid. Further, 9e underwent smooth
deacetylation, silylation, benzoylation, and silyl deprotection in
the presence of a TBAF buffer with HOAc to generate MBTG
alcohol 25. Silyl deprotection using MeOH/pTsOH was also
successful (see SI). TCAIs would show poor stability toward
any of the aforementioned conditions. Most importantly, we
demonstrated that activation of TCAIs in the presence of
MBTGs could be effected through control of temperature.
Glycosylation of MBTG acceptor 25 with TCAI 2614 using 10
mol % TMSOTf (64%) occurred without any detected
activation of the MBTG side chain at −20 °C. Our continuing
efforts will exploit this orthogonality with the further
elaboration of intermediates such as 27 and synthesis of
oligosaccharides utilizing the aforementioned latent-active
strategy.
Continuing studies demonstrated the efficacy of donor 9g6
(entries 8−10) while entries 10 and 11 demonstrate efficacy
with amino acid derived alcohols. Entry 8 suggests utility in the
preparation of acid-sensitive products such as 19. Finally, entry
12 demonstrates the utility of the 2-amino-2-deoxy donor 9h.
To further demonstrate the utility of MBTGs as
intermediates for synthesis, we performed a series of
transformations and a synthesis capitalizing on the orthogon-
ality of MBTGs to conditions that can activate TCAIs and
PTFAIs (Scheme 3). First, we synthesized 3-butenylthioglyco-
side 24 and determined that it is inert toward activation with
10 mol % HOTf in CH2Cl2. However, heating 24 in the
presence of 10 mol % of the second generation Grubbs catalyst
and 4-methoxystyrene in CH2Cl2 at reflux resulted in 9f (65%)
C
DOI: 10.1021/acs.orglett.8b02125
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Letter
ORCID
Toward the completion of this study, we synthesized 4-(4-
methoxyphenyl)-4-pentenylthioglycoside (MPTG) 28
(Scheme 4). Using conditions similar to the optimized
Justin R. Ragains: 0000-0002-2521-5396
Notes
Scheme 4. O-Glycosylation with MPTG Donor 28
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the National Science Foundation (CHE-
1665208) and Louisiana State University (LSU) for generous
support of this research. We thank Ms. Connie David (LSU)
for assistance with high resolution mass spectrometry.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jragains@lsu.edu.
D
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