MPTGs: Thioglycoside Donors for Acid-Catalyzed O-Glycosylation and Latent-Active Synthetic Strategies

Article abstract of DOI:10.1021/acs.orglett.8b03958

4-(p-Methoxyphenyl)-4-pentenylthioglycosides (MPTGs) undergo acid-catalyzed O-glycosylation with a range of alcohol acceptors in the presence of 10 mol % of triflic acid at room temperature. Particularly encouraging is the reactivity of MPTGs toward unrea

Full text of DOI:10.1021/acs.orglett.8b03958

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
MPTGs: Thioglycoside Donors for Acid-Catalyzed O‑Glycosylation
and Latent-Active Synthetic Strategies
Shaofu Du and Justin R. Ragains*
Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, United States
S
* Supporting Information
ABSTRACT: 4-(p-Methoxyphenyl)-4-pentenylthioglycosides
(MPTGs) undergo acid-catalyzed O-glycosylation with a
range of alcohol acceptors in the presence of 10 mol % of
triflic acid at room temperature. Particularly encouraging is the
reactivity of MPTGs toward unreactive acceptors. MPTGs can
be synthesized from the requisite vinyl bromides using the
Suzuki reaction, and this chemistry can be leveraged toward a
“latent-active” strategy for oligosaccharide synthesis.
activation occurred under relatively mild conditions at room
he microheterogeneity of oligosaccharides obtained from
Tnatural sources renders the isolation of pure samples for temperature, a departure from most methods for thioglycoside
biochemical characterization a difficult process.1 As a result,
activation that suggested the potential utility of MBTGs for
oligosaccharide synthesis. Acid-catalyzed activation of MBTGs
synthesis of oligosaccharides by enzymatic2 or chemical means
enabled high-yielding O-glycosylations at room temperature
and provided reactivity with a greater range of “armed” and
“disarmed” donors than photochemical activation.3h In
addition, MBTGs proved to be stable toward weaker acids
than HOTf (e.g., trifluoroacetic acid) and stable to a range of
other conditions3h that are compatible with thioglycosi-
des2c,3a−f,5 which, in turn, have proven to be a workhorse for
O-glycosylation and oligosaccharide synthesis. Nevertheless,
the reactivity of MBTGs toward poorly reactive alcohol
acceptors remained low.3h As such, we synthesized an
alternative 4-(p-methoxyphenyl)-4-pentenylthioglycoside
(MPTG, 1a, Scheme 1) and demonstrated its reactivity
toward a single hindered acceptor (α-methyl-2,3,6-tri-O-
benzylglucoside) in our initial report on acid catalysis.3h We
proposed that protonation of MPTGs (2) by acid catalyst
(resulting in 3° benzylic carbocation 3) was more facile than
protonation of MBTGs (resulting in a 2° benzylic
carbocation), and we surmised that this increase in reactivity
could translate to higher yields with hindered acceptors. In
support of the mechanistic proposal in Scheme 1, we were able
to isolate the heterocycle 6 from reaction mixtures.3h
is necessary for the unambiguous assignment of function. In
the realm of chemical synthesis, the development of effective
O-glycosylation electrophiles (glycosyl donors) and mild and
straightforward strategies for their activation remain important
endeavors for furthering glycoscience.3
We and others have shown that remote activation strategies
can be particularly effective for the activation of glycosyl
donors under relatively mild conditions that leave most other
functionalities unscathed.4 In particular, we recently intro-
duced 4-(p-methoxyphenyl)-3-butenylthioglycosides (MBTGs,
Scheme 1) first in the context of visible-light photochemical
activation3g and later in the context of acid-catalyzed activation
with trifluoromethanesulfonic acid (HOTf).3h Both modes of
Scheme 1. 4-(p-Methoxyphenyl)-3-butenylthioglycosides
and 4-(p-Methoxyphenyl)-4-pentenylthioglycosides
Herein, we demonstrate the reactivity of a range of “armed”
and “disarmed” MPTGs toward a host of alcohol acceptors of
varying reactivity at a 0.075 mmol scale and a single example at
a 1 mmol scale. Importantly, rates of activation are reasonable
regardless of the electron density at sulfur. In particular, we
demonstrate moderate- to high-yielding transformations with
very poorly reactive acceptors6 including the C4 hydroxyl
groups of glucuronic acid, glucose, and galactose. O-
Glycosylations with MPTGs work well at room temperature
Received: December 11, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03958
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
and are operatively straightforward. Like MBTGs, activation of
MPTGs with catalytic acid renders them compatible with
electroneutral alkenes, which is unusual for thioglycoside
activation.3a,b Perhaps most importantly, the structure of
MPTGs suggested a latent-active synthetic strategy (negating
concerns about a lack of differential reactivity among donors
with varying electron density at sulfur) that we put into action
with the synthesis of a model trisaccharide. This latent-active
strategy contributes to a growing arsenal of related methods in
the area of O-glycosylation.5c,7
acceptor at differing scales and dilutions provided inferior
yields (entries 5−8). In addition, diminished yields were
obtained with TMSOTf (entry 9). Surprisingly, attempts to
perform experiments at low temperature (0 and −20 °C)
provided complex mixtures with none of the expected product
8 (entries 10 and 11). Initially, we thought that poor reactivity
of acceptor toward unstable intermediates at these temper-
atures might explain this result. However, even methanol led to
similarly complex mixtures. Reasons for this outcome are
poorly understood at the moment.
Our initial development of MPTGs had not been subjected
to optimization,3h so we opted to look at the effects of various
parameters including concentration, ratio of MPTG/acceptor,
temperature, acid catalyst, and solvent using MPTG donor 1a.
As our initial report3h demonstrated near-quantitative yields
with the 6-position of methyl glucoside, we elected to pursue
optimization with the less reactive 4-position of methyl
glucoside using the acceptor α-methyl-2,3,6-tri-O-benzylgluco-
side (7, Table 1).
Continuing optimization demonstrated that a full equivalent
of HOTf was detrimental to the outcome (entry 12), while not
surprisingly, omission of HOTf resulted in no observed
conversion of 1a (entry 13). Further, screening of more
polar solvents (entries 14 and 15) yielded inferior results. In
addition, substitution of HOTf with trifluoroacetic acid
resulted in no detected conversion of 1a (entry 16), while
substitution of HOTf with HClO4 (entry 17) resulted in a
complex mixture containing unreacted 7 and small amounts of
8. As such, we opted to use conditions from entry 1 for
substrate scope studies. Finally, performance of this trans-
formation at a 1 mmol scale (1 mmol 7 and 1.5 mmol 1a, see
Supporting Information (SI) for details) resulted in 72% of 8.
Our substrate scope studies (Scheme 2) commenced with
tetrabenzoyl donor 1a and a series of secondary alcohol
acceptors. α-Methyl-3,4,6-tri-O-benzylglucoside afforded 81%
of the desired disaccharide (entry 1), while a galactose C4
acceptor (entry 2) and a glucuronic acid C4 acceptor (entry 3)
afforded moderate yields (54% and 59%, respectively) of
products. Given the exceptionally poor reactivity of these
acceptors,6 we found these results to be very encouraging and
indicative of the potential utility of MPTGs for the synthesis of
oligosaccharides. Continuing studies with tetrabenzyl MPTG
donor 1b and acceptors including the C6 acceptor α-methyl-
2,3,4-tri-O-benzylglucoside (entry 4), menthol (entry 5), 1-
adamantanol (entry 6), and cholesterol (entry 7) provided
good yields (74−83%) of O-glycosylation products, while
more difficult acceptors (tri-O-benzylated α-methylhexosides
like those used in entries 1−3) underwent O-glycosylation to
generate substantial quantities of the desired products
accompanied by unidentified and inseparable impurities. The
entry 7 (cholesterol) results demonstrate the compatibility of
electroneutral alkenes with this method.
We then synthesized 2-acetyl-3,4,6-tri-O-benzyl donor 1c
and tetraacetyl donor 1d and screened them with a series of
acceptors. Donor 1c provided a 68% yield of both disaccharide
products 16 and 17 when reacted with the C4 and C6 hydroxyl
groups of tri-O-benzyl-protected α-methyl glucoside acceptors
(entries 8 and 9), a 51% yield when reacting with the 4-
hydroxyl of benzyl-protected α-methyl galactoside (entry 10),
and a 62% yield when reacting with the 2-hydroxyl of α-methyl
3,4,6-tri-O-benzylglucoside (entry 11). As we and others have
shown,3h,8 tetraacetyl-protected donors are often poorly
behaved in glycosylation procedures. The tetraacetyl donor
1d was reacted with the C6 hydroxyl (entry 12) and the C4
hydroxyl (entry 13) of tri-O-benzyl-protected α-methyl
glucosides. Ironically, a yield of 35% was obtained in entry
12, whereas a yield of 57% was obtained in entry 13 with the
“more difficult” acceptor. It is possible that the higher yield in
the case of entry 13 is due to the less reactive C4 hydroxyl
being more selective toward the anomeric center of the
activated donor than the C6 hydroxyl in entry 12.
a
Table 1. Optimization
b
1
7
rxn temp
yield
(%)
entry (mmol) (mmol)
solvent
CH2Cl2
CH2Cl2 (2 mL)
CH2Cl2 (10 mL)
CH2Cl2
CH2Cl2
CH2Cl2 (2 mL)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
acetone
CH2Cl2
CH2Cl2
(°C)
1
2
3
4
5
6
7
8
9
0.15
0.15
0.15
0.38
0.075
0.075
0.1
0.12
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.075
0.075
0.075
0.19
0.075
0.075
0.1
20
20
20
20
20
20
20
20
20
0
−20
20
20
20
20
20
20
70
70
45
63
43
37
44
46
0.1
c
0.075
0.075
0.075
0.075
0.075
0.075
0.075
0.075
0.075
58
10
11
12
13
14
15
16
17
n.d.
nd
trace
nd
nd
nd
nd
n/a
d
e
a
Unless otherwise stated, the indicated amounts of donor 1a and
acceptor 7 were magnetically stirred with the indicated solvent (1 mL
unless explicitly stated (e.g., “CH2Cl2 (10 mL)” under the “solvent”
heading)) and 10 mol % of HOTf (relative to donor) at the indicated
b
c
temperature for 3 h. Isolated yields. Used 10 mol % of TMSOTf
d
e
instead of HOTf. Used trifluoroacetic acid instead of HOTf. Used
70% HClO4 instead of HOTf; nd, no product 8 detected; n/a, not
applicable/purification not performed.
Our initial studies of concentration demonstrated that 0.075
mmol of acceptor 7 with 0.15 mmol of tetrabenzoyl donor 1a
and 10 mol % of HOTf could provide high yields of
disaccharide 8 at 20 °C in either 1 or 2 mL of CH2Cl2
(70%, entries 1 and 2) but that further dilution (45%, 10 mL of
CH2Cl2) had a negative effect on yield (entry 3). Further,
while increasing the concentration of donor and acceptor in 1
mL of CH2Cl2 had, at best, a minor effect on yield (63%, entry
4), various attempts at using a ∼1:1 ratio of donor and
B
DOI: 10.1021/acs.orglett.8b03958
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Substrate Scope
Scheme 3. Latent-Active Strategy
a
Unless otherwise stated, 0.15 mmol of MPTG donor and 0.075
mmol of alcohol acceptor were used along with 10 mol % (relative to
donor) of HOTf and 1 mL of CH2Cl2 and the mixture stirred at 20
°C for 70 min or until alcohol had been consumed according to TLC
analysis. Then 20 mol % of Et3N (relative to donor) was added. After
evaporation, products were purified by silica gel chromatography and
yields of isolated products were determined.
demonstrating the potential efficacy of our “latent-active”
approach in the synthesis of complex targets.
In conclusion, we have demonstrated the efficacy of MPTGs
as donors in a range of O-glycosylation reactions. Reactions are
performed at room temperature, and high yields can be
obtained in the absence of molecular sieves. Further, we have
shown that the requisite latent vinyl bromide-bearing donors
can be converted to the active MPTGs via Suzuki coupling and
that this strategy could be applied toward the synthesis of a
model trisaccharide. Because of their reactivity toward
unreactive donors under user-friendly conditions and their
applicability toward “latent-active” strategies, we believe that
MPTGs are suitable for the synthesis of complex oligosac-
charides. Such studies are currently underway in our
laboratory.
With the establishment of substrate scope, we next pursued a
latent-active O-glycosylation exploiting structural features of
MPTGs. We noted that Pd-catalyzed cross-coupling could
potentially be used to establish the bond between the side-
chain alkene and the side-chain p-methoxyphenyl group of
MPTGs. We also surmised that the requisite vinyl halide-
bearing thioglycosides would be less reactive toward
protonation than MPTGs. As a proof of concept (Scheme
3), we synthesized vinyl bromide-bearing thioglycoside 22 and
demonstrated its poor reactivity toward our standard
conditions for MPTG activation (eq 1), establishing 22 as a
latent donor. Then 22 was subjected to Suzuki coupling with
p-methoxyphenylboronic acid (eq 2) to generate the active
MPTG donor. We were especially pleased with this result
given the potentially deleterious role of sulfur in Pd-catalyzed
cross-coupling reactions.
Given the aforementioned successes, we put our latent-
active strategy into action (Scheme 3) with the synthesis of a
model trisaccharide. Coupling of MPTG 1a with latent
thioglycoside acceptor 23 resulted in a 78% yield of “latent”
disaccharide 24. Subsequent Suzuki coupling of 24 with p-
methoxyphenylboronic acid afforded “active” donor 25. O-
Glycosylation of α-methyl 2,3,4-tri-O-benzylglucoside with an
excess of 25 subsequently afforded 75% of trisaccharide 26,
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.8b03958.
1
Experimental procedures, characterization data, H and
13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jragains@lsu.edu.
ORCID
Justin R. Ragains: 0000-0002-2521-5396
C
DOI: 10.1021/acs.orglett.8b03958
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(8) Kondo, H.; Aoki, S.; Ichikawa, Y.; Halcomb, R. L.; Ritzen, H.;
Wong, C.-H. J. Org. Chem. 1994, 59, 864.
Notes
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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DOI: 10.1021/acs.orglett.8b03958
Org. Lett. XXXX, XXX, XXX−XXX