Gold-catalyzed synthesis of 2-deoxy glycosides using S-But-3-ynyl thioglycoside donors

Article abstract of DOI:10.1021/cs300670k

A mild and atom-economic gold(I)-catalyzed glycosylation for stereoselective synthesis of 2-deoxy α- glycosides using bench-stable 2-deoxy S-But-3-ynyl thioglycoside donors has been described. Under optimal conditions, 2- deoxy and 2,6-dideoxy thioglycoside donors were able to react with a variety of primary, secondary, and tertiary alcohol acceptors to afford α-selective glycosides in good to excellent yields.

Full text of DOI:10.1021/cs300670k

Research Article
pubs.acs.org/acscatalysis
Gold-Catalyzed Synthesis of 2‑Deoxy Glycosides Using S‑But-3-ynyl
Thioglycoside Donors
Surya Adhikari, Kedar N. Baryal, Danyang Zhu, Xiaohua Li, and Jianglong Zhu*
Department of Chemistry and School of Green Chemistry and Engineering, The University of Toledo, 2801 West Bancroft Street,
Toledo, Ohio 43606, United States
S
* Supporting Information
ABSTRACT: A mild and atom-economic gold(I)-catalyzed
glycosylation for stereoselective synthesis of 2-deoxy α-
glycosides using bench-stable 2-deoxy S-But-3-ynyl thioglyco-
side donors has been described. Under optimal conditions, 2-
deoxy and 2,6-dideoxy thioglycoside donors were able to react
with a variety of primary, secondary, and tertiary alcohol
acceptors to afford α-selective glycosides in good to excellent yields.
KEYWORDS: gold, homogeneous catalysis, alkyne, glycosylation, 2-deoxy glycosides
2-Deoxy sugars exist in a wide range of bioactive natural
molecules and have been found to play a critical role in their
biological activities.1−3 Consequently, a great deal of studies for
the synthesis of 2-deoxy glycosides have been reported over
recent decades.4−6 Nevertheless, stereoselective construction of
a 2-deoxy glycosidic linkage remains challenging because of the
absence of a directing group at C-2, despite the availability of
numerous glycosylation protocols.7 A most common strategy
for stereoselective preparation of 2-deoxy sugars involves the
installation of a directing group at C-2, followed by its removal
after glycosylation.4−6,8−19 In addition, other methods have
been developed for stereoselective synthesis of 2-deoxy
glycosides using glycosyl phosphites,20,21 glycosyl halides,22,23
glycosyl imidates,24 (2′-carboxy)benzyl-4,6-O-benzylidene-2-
deoxyglucoside,25 3,4-O-carbonate-protected thioglycosides,26
dehydrative glycosylation of lactol,27 and alkoxy-substituted
anomeric radical,28,29 as well as anomeric O-alkylation.30
Recently, transition-metal catalysis has been successfully
applied to the stereoselective synthesis of O-glycosides
including 2-deoxy sugars.31,32 In general, use of catalytic
amounts of transition-metal complex as promoter provided a
“green”, mild, and orthogonal alternative approach to the
traditional glycosylation. In some cases, anomeric selectivity can
be controlled by careful selection of the ligand coordinating to
the transition metal rather than substrate control or directed by
the coordinating ability of the transition metal to the
heteroatoms (e.g., oxygen and nitrogen) of glycosyl donors
and acceptors. For instance, O'Doherty reported stereoselective
synthesis of 2-deoxy sugars using palladium-catalyzed O-
glycosylations of 6-tert-butoxycarboxy-2H-pyran-3(6H)-ones
followed by functionalization.33 In 2004, Toste disclosed a
rhenium(V)-catalyzed selective formation of 2-deoxy α-glyco-
sides from “armed” glycals.34 Later, in 2009, Nguyen reported a
cationic palladium(II)-catalyzed synthesis of 2-deoxy glycoside
using 2-deoxy glycosyl trichloroacetimidate donor.35 Most
recently, Yu developed a gold(I)-catalyzed synthesis of 2-
deoxy glycosides using 2-deoxy ortho-alkynylbenzoate do-
nors.36,37
Given the aforementioned merits, our group has also been
interested in developing mild and atom-economic transition-
metal-catalyzed O-glycosylations for synthesis of 2-deoxy
glycosides using readily available and bench-stable glycosyl
donors. Along with this direction, we became enamored of the
O-glycosylations via homogeneous cationic gold(I)-catalyzed
selective activation of the alkyne functionality reported by Yu
group,36−38 but with an aim of development of 2-deoxy glycosyl
donors bearing a simple alkyne-containing leaving group.39,40
On the basis of the observation from Yu and co-workers,36,37
we speculated that 2-deoxy S-but-3-ynyl thioglycosides (cf. 1,
Scheme 1) bearing a more nucleophilic sulfur38,41,42 atom may
Scheme 1. Au(I)-Catalyzed Synthesis of 2-Deoxy Glycosides
Using S-But-3-ynyl Thioglycosides
likely attack the activated alkyne for anomeric ionization to
facilitate the subsequent glycosylation. In addition, it is well-
known that thioglycosides7 are stable and survive in a variety of
transformations, including protecting group manipulations.
Peracetylated 2-deoxy S-but-3-ynyl thioglycosides (1a−d)
can be conveniently prepared as a mixture of anomers in one
step from readily available 2-deoxy glycosyl acetates (3a−d)
and 3-butyn-1-thiol43 (4) in the presence of boron trifluoride
diethyl etherate under standard conditions (Table 1).44 In
addition, 1a was converted to the perbenzylated donor 1e in
Received: October 13, 2012
Revised: November 26, 2012
© XXXX American Chemical Society
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Research Article
a
catalyst loading to 5 mol % led to 95% conversion and 92%
isolated yield with 3/1 α/β selectivity (entry 6). This anomeric
selectivity was not totally unexpected, provided that there is no
participating group present at C-2. It was further found that use
of excess AgOTf was able to promote this reaction to
completion in 30 min with 99% isolated yield of 2-deoxy
disaccharide 7 (entry 7), probably as a result of the silver effect
in gold catalysis.47 It is also possible that excess silver triflate
may partially hydrolyze to triflic acid, which facilitates
protodeauration and regeneration of the cationic gold(I)
catalyst. We also investigated the reaction using pure 1aα and
1aβ separately and found that they gave comparable
experimental outcomes, although 1aα was found to be a little
more reactive than its β counterpart.48 Therefore, a mixture of
1α and 1β was subsequently employed in this type of O-
glycosylation reactions.
Table 1. Synthesis of 2-Deoxy- S-But-3-ynyl Thioglycosides
a
General conditions: peracetate (1.0 equiv), 3-butyn-1-thiol (2.0
equiv), BF3·Et2O (2.0 equiv), CH2Cl2, 0 °C to RT, 30 min.
Lowering gold catalyst loading to 2.5 mol % required a much
longer reaction time to achieve comparable results (entry 8).
This gold(I)-catalyzed reaction seemed to be fast initially and
sluggish after some time. It was not surprising to us that no
reaction occurred without gold(I) catalyst (entry 9). In
contrast, use of 2-deoxy-but-3-ynyl D-glucoside donor (5)
under optimal conditions did not afford any desired product
(entry 10), which was consistent with the observation by Yu
and co-workers.36 These experiments demonstrate the higher
reactivity of thioglycoside, probably due to the more
nucleophilic nature of the sulfur atom over oxygen.
two steps (82% overall yield), and 1b was converted to donor
1f in three steps (70% overall yield).44 We also prepared an
analogous 2-deoxy but-3-ynyl glucoside donor 545 for
comparing its reactivity with 1a toward gold(I) catalysis.
The reaction between 2-deoxy S-but-3-ynyl D-thioglucoside,
1a, and diacetone D-galactose, 6, was first studied under gold(I)
catalysis (Table 2). Initially, it was found that neither Ph3PAuCl
Table 2. Optimization of Gold(I)-Catalyzed O-
a
Glycosylation
With this optimal condition developed, we next investigated
the reaction scope using 2-deoxy S-but-3-ynyl thioglycosides
(1a−b, e−f) and a variety of alcohol acceptors. As shown in
Table 3, both peracetylated and perbenzylated 2-deoxy S-but-3-
ynyl D-thioglucosides (1a and 1e) reacted with primary,
b
c
entry
reaction conditions
2.5 mol % Ph3PAuCl
yield (α/β)
Table 3. Gold(I)-Catalyzed Synthesis of 2-Deoxy
Glycosides
1
2
3
4
<1%
a
2.5 mol % Ph3PAuNTf2
<1%
2.5 mol % Ph3PAuCl, 2.5 mol % AgOTf
2.5 mol % (4-CF3−Ph)3PAuCl, 2.5 mol % AgOTf
2.5 mol % (4-CF3−Ph)3PAuCl, 2.5 mol % AgOTf
5 mol % (4-CF3−Ph)3PAuCl, 5 mol % AgOTf
5 mol % (4-CF3−Ph)3PAuCl, 10 mol % AgOTf
2.5 mol % (4-CF3−Ph)3PAuCl, 10 mol % AgOTf
10 mol % AgOTf, RT, 48 h
12% conv
18% conv
47% conv
92% (3:1)
99% (3:1)
99% (3:1)
d
5
e
6
f
7
g
8
9
no reaction
no reaction
h
10
5 mol % (4-CF3−Ph)3PAuCl, 10 mol % AgOTf
a
Reactions were performed using 0.1 mmol of 6, 0.12 mmol of 1a (1.2
equiv), gold and/or silver catalyst in 1 mL of anhydrous CH2Cl2 in the
presence of 4 Å molecular sieves at room temperature for 6 h unless
b
c
1
otherwise noted. Isolated yield. α/β ratio was determined by H
d
e
NMR analysis. Addition of 5 mol % triflic acid. 95% conversion was
observed. Reaction was complete in 30 min. Reaction required 22 h
to complete. 2-Deoxy-3-butynyl-D-glucoside donor 5 was used,
f
g
h
reaction was performed at room temperature or 40 °C.
nor Ph3PAuNTf2 was effective catalyst for this type of O-
glycosylation (entries 1−2). Use of 2.5 mol % cationic gold(I)
complex Ph3PAuOTf, prepared from Ph3PAuCl and AgOTf,
was able to catalyze this glycosylation and gave 12% conversion
in 6 h (entry 3). Variation of phosphine ligand from PPh3 to (4-
CF3−Ph)3P46 in the cationic gold(I) complex slightly improved
the conversion to 18% (entry 4). Addition of 5 mol % triflic
acid in this reaction increased the yield to 47% conversion
(entry 5), probably because of facilitation of protodeauration
and regeneration of the cationic gold(I) catalyst. Increasing the
a
General conditions: a mixture of 0.1 mmol of alcohol acceptor, 0.12
mmol of thioglycoside donor 1 (1.2 equiv), 5 mol % (4-CF3−
Ph)3PAuCl, and 10 mol % AgOTf, and 4 Å molecular sieves in 1 mL of
anhydrous CH2Cl2 was stirred at room temperature for 30 min.
b
Yields based on recovered acceptors are reported in the parentheses.
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secondary, and tertiary alcohol acceptors to afford desired
disaccharides and glycoconjugates 8−12 in moderate α-
selectivity and good to excellent yields. Use of peracetylated
2-deoxy S-but-3-ynyl D-thiogalactoside donor 1b and related
donor 1f in this cationic gold(I)-catalyzed glycosylation
provided the desired disaccharides and glycosconjugates 13−
18 in good to excellent α-selectivity and yields.
On the basis of the fact that 2,3-dihydrothiophene was
identified as the byproduct,44 a plausible mechanism is
proposed for this cationic gold(I)-catalyzed glycosylation. As
shown in Scheme 3, activation of the alkyne functionality of S-
Scheme 3. Proposed Mechanism
We also investigated 2,6-dideoxy S-but-3-ynyl thioglycosides
in this cationic gold(I) catalysis because of their presence in a
variety of bioactive natural molecules.1−3 As depicted in Table
4, under optimal conditions, peracetylated S-but-3-ynyl L-
Table 4. Gold(I)-Catalyzed Synthesis of 2,6-Dideoxy
a
Glycosides
but-3-ynyl thioglycoside 1a by cationic gold(I) catalyst followed
by attack of an exo sulfur atom provides sulfonium ion 31.38
Subsequent cleavage of the glycosidic bond of 31 results in the
formation of oxocarbenium ion 32 and 2,3-dihydrothiophene-
4-yl-gold(I) complex 33. Glycosylation of 32 with an alcohol
acceptor furnishes the desired 2-deoxy glycoside and a molecule
of triflic acid. Protodenauration of 2,3-dihydrothiophen-4-yl-
gold(I) complex 33 leads to the formation of 2,3-
dihydrothiophene 30 and regeneration of the cationic gold(I)
catalyst.
In conclusion, we have developed a mild and atom-economic
cationic gold(I)-catalyzed O-glycosylation for selective syn-
thesis of 2-deoxy and 2,6-dideoxy α-glycosides using 2-deoxy S-
but-3-ynyl thioglycoside donors. This glycosylation is amenable
to a variety of aliphatic alcohol acceptors, including
carbohydrate-derived primary and secondary hydroxyl groups.
Experimental results indicated that 2,3-dihydrothiophene was
formed as a byproduct in this cationic gold(I)-catalyzed O-
glycosylation. Studies toward stereoselective synthesis of other
types of oligosaccharides via gold catalysis using S-but-3-ynyl
thioglycoside donors are currently in progress and will be
reported in due course.
a
General conditions: a mixture of 0.1 mmol of alcohol acceptor, 0.12
mmol of thioglycoside donor 1 (1.2 equiv), 5 mol % (4-CF3−
Ph)3PAuCl, and 10 mol % AgOTf, and 4 Å molecular sieves in 1 mL of
anhydrous CH2Cl2 was stirred at room temperature for 30 min.
b
Yields based on recovered acceptors are reported in the parentheses.
olivoside 1c was able to react with various alcohol acceptors to
afford the desired disaccharides and glycoconjugates 19−23 in
moderate to good α-selectivity and excellent yields. Similarly,
peracetylated S-but-3-ynyl L-olioside 1d reacted with these
alcohol acceptors to provide the desired disaccharides and
glycoconjugates 24−27 in good to excellent α-selectivity and
yields.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedure and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
Because of the difficulty in characterizing the volatile
byproduct 2,3-dihydrothiophene 30 in the glycosylation
reactions, methoxymethyl 3-butynylthioether 28 was pre-
pared44 and subjected to our optimal cationic gold(I) catalysis
in deuterated chloroform (CDCl3) in the presence of a slight
excess of methanol (Scheme 2). The reaction was monitored
using 1H NMR and found to cleanly afford the desired product
dimethoxymethane 29 and byproduct 2,3-dihydrothiophene 30.
2,3-Dihydrothiophene 30 was unambiguously characterized
AUTHOR INFORMATION
Corresponding Author
*E-mail: Jianglong.Zhu@Utoledo.edu.
■
Notes
The authors declare no competing financial interest.
through analysis of the H and 13C NMR, HSQC, and mass
1
ACKNOWLEDGMENTS
■
spectra.44
Start-up funding from The University of Toledo is gratefully
acknowledged. This work was presented in part at the 244th
American Chemical Society National Meeting, Philadelphia,
PA, United States, August 19−23, 2012, CARB-15.
Scheme 2. Identification of Byproduct 2,3-
Dihydrothiophene
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