AuCl3- and AuCl3-Phenylacetylene-Catalyzed Glycosylations by Using Glycosyl Trichloroacetimidates

Article abstract of DOI:10.1002/ejoc.201500137

Glycosylations of armed and disarmed trichloroacetimidate-based glycosyl donors were carried out by using the AuCl₃-phenylacetylene relay catalyst system. The effectiveness of this catalytic system was also compared with that of using AuCl₃ alone as a catalyst. Glycosylations with these catalysts proceeded efficiently at room temperature within 5-45 min. Excellent diastereoselectivity was obtained for the glycosylation of 2-O-acetyl-protected disarmed glycosyl donors, whereas armed glycosyl trichloroacetimidates gave rise to a mixture of anomeric glycosides. Acid-sensitive nucleophiles such as Fmoc-serine tert-butyl ester or Fmoc-threonine tert-butyl ester successfully underwent the glycosylations, albeit in moderate yields, under mild conditions at room temperature. We have reported a convenient room temperature protocol that employs AuCl₃ and phenylacetylene as a catalyst system to carry out the glycosylation of glycosyl trichloroacetimidates. The effectiveness of this relay catalyst system was also compared with that of using AuCl₃ alone to catalyze the glycosylations.

Full text of DOI:10.1002/ejoc.201500137

FULL PAPER
DOI: 10.1002/ejoc.201500137
AuCl3– and AuCl3–Phenylacetylene-Catalyzed Glycosylations by Using
Glycosyl Trichloroacetimidates
Rashmi Roy,[a] Ashok Kumar Palanivel,[a] Asadulla Mallick,[a] and Yashwant D. Vankar*[a]
Keywords: Synthetic methods / Homogeneous catalysis / Gold / Glycosylation / Glycosides / Carbohydrates / Amino acids
Glycosylations of armed and disarmed trichloroacetimidate-
based glycosyl donors were carried out by using the AuCl3–
phenylacetylene relay catalyst system. The effectiveness of
this catalytic system was also compared with that of using
AuCl3 alone as a catalyst. Glycosylations with these catalysts
proceeded efficiently at room temperature within 5–45 min.
Excellent diastereoselectivity was obtained for the glycosyl-
ation of 2-O-acetyl-protected disarmed glycosyl donors,
whereas armed glycosyl trichloroacetimidates gave rise to a
mixture of anomeric glycosides. Acid-sensitive nucleophiles
such as Fmoc-serine tert-butyl ester or Fmoc-threonine tert-
butyl ester successfully underwent the glycosylations, albeit
in moderate yields, under mild conditions at room tempera-
ture.
BF3·OEt2,[8]
trimethylsilyl
trifluoromethanesulfonate
Introduction
(TMSOTf),[9] HClO4-silica gel,[10] InCl3,[11] AgOTf,[12]
LiOTf,[13] and sulfated zirconia in supercritical (sc) CO2.[14]
In many cases, however, low temperatures are required for
glycosylation to take place with glycosyl trichloroacetimid-
ates. Moreover, some of these reactions specifically need to
be conducted with some specific catalyst.[12] Thus, it is im-
portant to discover mild reagent systems and user friendly
protocols to carry out glycosylations of trichloroacetimid-
ate-based glycosyl donors at room temperature.
Glycoproteins, glycolipids, and oligosaccharides are
found in abundance at the outer surface of the cell mem-
brane and play an important role in fundamental cell re-
cognition processes.[1] Moreover, in biological processes, the
functions of oligosaccharides involve the development and
survival of an organism.[2] In living systems, protein glyc-
osylation is a crucial post-translational process to impart
structural stability to a native protein.[3] In the last few dec-
ades, extensive studies have been done to introduce new
glycosylation methodologies[4] with the goal to improve
their synthetic repertoire, which should be useful for the
syntheses of biologically important oligosaccharides,[5]
glycopeptides,[6a–6c] and glycolipids.[6d] Glycosyl trichloro-
acetimidates, which were introduced by Schmidt and
Michel,[7] are one of the most efficient glycosyl donors for
glycosylation reactions. The glycosyl trichloroacetimidates
are not only easy to prepare and handle but also generally
lead to the glycosylated products in high yields and excel-
lent stereoselectivity.[7] For example, the synthesis of a
tumor-associated mucin glycopeptide by Danishefsky et
al.[8] involved O-glycosylation with a trichloroacetimidate
donor as a crucial step. A recent report of the preparation
of an anthrose analogue by Grandjean et al.[9] involves the
use of trichloroacetimidate donors to carry out glycosyl-
ation reactions. Popular promoters of the glycosylation of
trichloroacetimidate donors include both protic as well as
Lewis acids such as p-toluenesulfonic acid (TsOH),[7]
In recent years, gold-catalyzed glycosylations have gained
importance, and a few interesting glycosyl donors have been
introduced[15] for this purpose, keeping in mind the alkyno-
philicity of gold salts. Interestingly, Kunz and co-workers
have reported a clever use of AuCl-catalyzed glycosylations
by using glycosyl trichloroacetimidates at room tempera-
ture.[16] Recently, we reported about gold(III) chloride–
phenylacetylene as an efficient catalytic system for the
glycosylation of 1-O-acetyl sugars as well as for Ferrier re-
arrangements of glycals and 2-acetoxymethyl glycals.[17]
Furthermore, we discovered that AuCl3 and AuCl3–phenyl-
acetylene catalyst systems activate trichloroacetimidate
glycosyl donors at room temperature to form O-glycosides.
Results and Discussion
We performed a comparative glycosylation study in the
presence of the AuCl3–phenylacetylene and AuCl3 catalyst
systems by using disarmed trichloroacetimidate glycosyl do-
nors 1 and 2 and armed glycosyl donor 3[7] with a range of
nonsugar (i.e., 4, 5, 6, 18, and 25), sugar-derived[18] (i.e., 7
and 8), and amino acid derived[19] (i.e., 9, 10, and 26)
alcohols as depicted in Scheme 1. The reaction of trichloro-
acetimidate 1 with allyl alcohol (4) smoothly underwent a
[a] Department of Chemistry, Indian Institute of Technology
Kanpur,
Kanpur, Uttar Pradesh 208016, India
E-mail: vankar@iitk.ac.in
http://home.iitk.ac.in/~vankar/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500137.
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AuCl3– and AuCl3–Phenylacetylene-Catalyzed Glycosylations
reaction within 10 min to afford glycoside 11[11] in 95%
yield by using the AuCl3–phenylacetylene catalyst system.
In contrast, when the same reaction was conducted in the
absence of phenylacetylene, glycoside 11 was formed within
10 min but only in 66% yield (Table 1, Entry 1). Thus, the
AuCl3–phenylacetylene combination is a more effective cat-
alyst system than AuCl3 alone as far as yield is concerned.
Similarly, in the case of benzyl alcohol (5) and menthol (6)
as glycosyl acceptors, the yields of the products 12[16] and
13[20] increased from 55 and 70% to 89 and 85%, respec-
tively, when the AuCl3–phenylacetylene catalyst system was
employed (Table 1, Entries 2 and 3). These are improved
results compared to an AuCl-catalyzed glycosylation,[16] in
which 1 was treated with 5 to form 12 in 2 h in 71% yield.
Scheme 1. Glycosylation of 1–3 with acceptors 4–10, 18, 25, and 26.
Table 1. Synthesis of glycosides 11–17 by using nucleophiles 4–10 and disarmed glycosyl donor 1 in dichloromethane at room tempera-
ture.[a]
[a] Room temperature was 35–39 °C. Reactions were performed by using AuCl3 (3 mol-%) and phenylacetylene (3 mol-%) or by using
1
only AuCl3 (3 mol-%). [b] Isolated yield. [c] The α/β ratio was determined by H NMR spectroscopic analysis. [d] Fmoc = 9-fluorenyl-
methoxycarbonyl.
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R. Roy, A. K. Palanivel, A. Mallick, Y. D. Vankar
FULL PAPER
Similar trends were observed when sugar-derived alcohols
Next, galactose-derived trichloroacetimidate disarmed
7 and 8 were employed in the glycosylation to obtain 14[21] glycosyl donor 2 was subjected to the glycosylation reac-
and 15,[22] respectively (Table 1, Entries 4 and 5). There- tions in the presence of this newly developed catalyst sys-
after, we focused our attention on the glycosylations of tem. Thus, under the AuCl3–phenylacetylene catalytic sys-
serine- and threonine-derived alcohols 9 and 10. In the tem, 2 was treated with benzyl alcohol (5) at room tempera-
presence of the AuCl3–phenylacetylene catalyst system, ture in dichloromethane to afford only the β anomer of
glycosides 16 and 17 were formed (see Experimental Section glycoside 19[16] within 10 min in 81% yield (Table 2, En-
for data) in 45 and 52% yield, respectively. Although the try 1). In contrast, in the presence of AuCl3 alone, the reac-
yield of compound 16 was same in the presence of either tion reached completion within 10 min but led to a rela-
the AuCl3 catalyst or the AuCl3–phenylacetylene catalyst tively lower yield of 50% (Table 2, Entry 1). However both
system, the yield of compound 17 significantly decreased to reactions were faster than the AuCl-catalyzed version,[16] in
15% when AlCl3 was used alone (Table 1, Entries 6 and 7). which the reaction time was reported to be 3 h. Likewise,
Apart from alcohols 7 and 10 (Table 1, Entries 4 and 7), the when the reaction of 2 and cyclohexanol 18 was catalyzed
remainder of the nucleophiles led to the formation of only by AuCl3–phenylacetylene at room temperature, it gave rise
β-glycosides when AuCl3–phenylacetylene was used as the to glycoside 20[23] with exclusive formation of the β product
catalyst (Table 1, Entries 1, 2, 3, 5, and 6). Moreover, this β- in 83% yield after 10 min (Table 2, Entry 2). The reactions
selectivity was more pronounced in the presence of AuCl3– between 2 and sugar-derived alcohols 7 and 8 reached com-
phenylacetylene compared with AuCl3 alone (Table 1, En- pletion in 7 and 5 min, respectively, and led to products
tries 3, 4, and 7).
21[23,24] and 22[24] (Table 2, Entries 3 and 4) in reasonably
Table 2. Synthesis of glycosides 19–24 by using nucleophiles 5, 18, and 7–10 and disarmed glycosyl donor 2 in dichloromethane at room
temperature.[a]
[a] Room temperature was 35–39 °C. Reactions were performed by using AuCl3 (3 mol-%) and phenylacetylene (3 mol-%) or by using
1
only AuCl3 (3 mol-%). [b] Isolated yield. [c] The α/β ratio was determined by H NMR spectroscopic analysis.
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AuCl3– and AuCl3–Phenylacetylene-Catalyzed Glycosylations
good yields. On the other hand, in presence of the AuCl3–
phenylacetylene catalyst system, the reaction of glycosyl do-
nor 2 and amino acid derived alcohols 9 and 10 furnished
glycosides 23 and 24 in 10 and 5 min and in 50 and 47%
yield, respectively (Table 2, Entries 5 and 6).
The better yields of product formation in the presence of
AuCl3–phenylacetylene compared with those in the pres-
ence of only AuCl3 can be explained by a relay catalysis
system (Figure 1). Thus, AuCl3 along with phenylacetylene
forms a relay catalyst entity, which can drive glycosylations
of trichloroacetimidate donors in a more efficient manner
than AuCl3 alone, as found in our earlier observations of
1-O-acetyl glycosyl donors.[17,25] However, it is possible that
direct activation of the trichloroacetimidate moiety of the
glycosyl donors with AuCl3 also occurs to lead to the
glycosylated products. At the same time, it is also likely that
under these conditions direct activation of the trichloroacet-
imidate moiety with AuCl3 might lead to decomposition or
side product formation, which would result in a decreased
yield of glycosylated products. Glycosylations of 1 and 2
led to β-glycosides either exclusively or as the major prod-
Figure 1. Mechanism of AuCl3–phenylacetylene-catalyzed glycosyl-
ations of trichloroacetimidates.[25]
uct, which is a result of the neighboring group participation cosides 27–31,[26] respectively. In all of the cases, the yields
by the –OAc group at the C-2 atom. were higher by using the AuCl3–phenylacetylene catalyst
Thereafter, armed trichloroacetimidate glycosyl donor 3 system than by using only AuCl3 (Table 3, Entries 1–5). The
was subjected to the glycosylation reactions in the presence glycosylations of 3 resulted in lower diastereoselectivities
of glycosyl acceptors 6, 25, 7, 8, and 26 to form the gly- because of the lack of neighboring group participation.
Table 3. Synthesis of glycosides 27–31 by using nucleophiles 6–8, 25, and 26 and disarmed glycosyl donor 3 in dichloromethane at room
temperature.[a]
[a] Room temperature was 35–39 °C. Reactions were performed by using AuCl3 (3 mol-%) and phenylacetylene (3 mol-%) or by using
1
only AuCl3 (3 mol-%). [b] Isolated yield. [c] The α/β ratio was determined by H NMR spectroscopic analysis. [d] The α and β anomers
were separated by column chromatography. [e] Cbz = benzyloxycarbonyl.
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R. Roy, A. K. Palanivel, A. Mallick, Y. D. Vankar
FULL PAPER
N-(9-Fluorenylmethyloxycarbonyl)-O-(2,3,4,6-tetra-O-acetyl-
D-
Conclusions
glucopyranosyl)- -threonine tert-Butyl Ester (17): Yellowish oil
L
In summary, both AuCl3 and the AuCl3–phenylacetylene (52% yield); Rf = 0.42 (hexane/ethyl acetate, 6.5:3.5). [α]2D0 = +7.04
(c = 0.27, CH Cl ). IR (neat): ν = 741, 1061, 1222, 1369, 1450,
˜
max
combination were efficient catalysts for the glycosylations
of both armed and disarmed trichloroacetimidate glycosyl
donors. However, the AuCl3–phenylacetylene catalyst pro-
vided better product yields in most cases (Tables 1, 2, and
3). Acid-sensitive groups, such as the tert-butyl ester moiety
in 9 and 10, were unaffected by the mild reaction conditions
of the glycosylations.
2
2
1750, 2978, 3374 cm–1. 1H NMR (500 MHz, CDCl3, 1:6 mixture
of diastereomers): δ = 1.18 (d, J = 6.0 Hz, 3 H, Me, β isomer), 1.34
(d, J = 6.0 Hz, 3 H, Me, α isomer), 1.44 (s, 9 H, tBu, α isomer),
1.47 (s, 9 H, tBu, β isomer), 1.99–2.15 (m, 24 H, OAc, both iso-
mers), 3.88 (t, J = 6.4 Hz, 1 H, CHNHFMoc, β isomer), 3.95 (t, J
= 6.4 Hz, 1 H, CHNHFMoc, α isomer), 4.07–4.11 (m, 3 H,
CH2CHNHFMoc, 6-Ha, both isomers), 4.21–4.26 (m, 2 H, Thr-α-
H, 6-Hb, both isomers), 4.31–4.47 (m, 3 H, 4-H, 5-H, Thr-β-H,
both isomers), 4.91 (dd, J = 2.4, 10.8 Hz, 1 H, 2-H, α isomer), 5.00
(dd, J = 3.2, 10.8 Hz, 1 H, 2-H, β isomer), 5.11 (dd, J = 7.6,
10.8 Hz, 1 H, 3-H, β isomer), 5.17 (dd, J = 3.8, 12.4 Hz, 1 H, 3-H,
α isomer), 5.28–5.36 (m, 1 H, 1-H, both isomers), 5.52 (d, J =
9.6 Hz, 1 H, NH, β isomer), 5.65 (d, J = 6 Hz, 1 H, NH, α isomer),
7.31–7.76 (m, 16 H, Ar, both isomers) ppm. 13C NMR (125 MHz,
CDCl3): δ = 16.1, 20.7, 20.7, 20.8, 27.9, 28.1, 47.2, 58.8, 61.2, 66.9,
67.2, 69.0, 70.6, 70.7, 73.7, 82.3, 98.0, 120.0, 125.3, 125.4, 127.1,
127.7, 141.3, 143.8, 144.1, 156.8, 168.8, 169.4, 170.2, 170.5 ppm.
HRMS: calcd. for C37H46NO14 [M + H]+ 728.2918; found
728.2919.
Experimental Section
General Methods: AuCl3 and phenylacetylene were purchased from
Sigma–Aldrich and Lancaster Synthesis, respectively. Trichloroace-
timidate glycosyl donors 1, 2, and 3[27] were prepared by a standard
literature procedure.[7] Sugar-derived glycosyl acceptors 7 and 8
were synthesized according to standard literature procedures.[18]
Amino acid derived nucleophiles were synthesized according to lit-
erature procedures.[19]
General Procedure for AuCl3-Phenylacetylene-Catalyzed Glycosyl-
ation of Glycosyl Trichloroacetimidates: To a solution of 1 or 2
(200 mg, 0.4 mmol) or 3 (200 mg, 0.3 mmol) in anhydrous CH2Cl2
(1.5 mL) was added a glycosyl acceptor (0.48 mmol) followed by
the addition of AuCl3 (3 mol-%) and phenylacetylene (3 mol-%) at
room temperature and then molecular sieves (4 Å). The reaction
was allowed to continue at room temperature until the starting ma-
terial was consumed (monitored by TLC analysis). When the reac-
tion reached completion, it was immediately quenched by the ad-
dition of water, and the resulting solution was extracted with
dichloromethane (2ϫ 3 mL). The combined organic layers were
dried with anhydrous Na2SO4, and the solvents were evaporated to
dryness under vacuum to obtain the crude glycosides. The crude
products were then purified by silica gel column chromatography
(hexane and ethyl acetate) to afford glycosides 11 (148 mg, 95%),
12 (150 mg, 89%), 13 (166 mg, 85%), 14 (274 mg, 86%), 15
(238 mg, 75%), 16 (128 mg, 45%), 17 (152 mg, 52%), 19 (142 mg,
81%), 20 (142 mg, 83%), 21 (228 mg, 72%), 22 (190 mg, 60%), 23
(144 mg, 50%), 24 (136 mg, 47%), 27 (172 mg, 85%), 28 (204 mg,
75%), 29 (246 mg, 83%), 30 (222 mg, 75%), 31 (154 mg, 66%).
Data for known glycosides 11–15, 19–24, and 27–31 were in agree-
ment with data from the literature.[10,11,16,20–24] Analytical data for
glycosides 16 and 17 are given below.
Acknowledgments
The authors thank the Department of Science and Technology
(DST), New Delhi for the J. C. Bose National Fellowship to
Y. D. V. (JCB/SR/S2/JCB-26/2010) and the Council of Scientific
and Industrial Research (CSIR), New Delhi for financial support
through grant number 02(0124)/13/EMR-II. R. R. thanks the Uni-
versity Grants Commission (UGC), New Delhi and A. K. P. and
A. M. thank CSIR for their senior research fellowships.
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CH2CHNHFMoc), 4.92 (t, J = 9.0 Hz, 1 H, 2-H), 5.05 (t, J =
9.7 Hz, 1 H, 4-H), 5.19 (t, J = 9.7 Hz, 1 H, 3-H), 5.57 (d, J =
7.9 Hz, 1 H, NH), 7.30–7.77 (m, 8 H, Ar) ppm. 13C NMR
(125 MHz, CDCl3): δ = 20.6, 20.6, 20.7, 27.9, 28.0, 47.2, 54.9, 61.9,
67.0, 68.3, 70.0, 71.3, 71.8, 72.7, 83.0, 101.1, 120.1, 125.1, 127.1,
127.8, 141.4, 143.7, 143.9, 155.8, 168.3, 169.2, 169.5, 170.3,
170.7 ppm. HRMS: calcd. for C36H44NO14 [M + H]+ 714.2756;
found 714.2759.
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mally appears as a singlet at δ = 3.1 ppm, appeared as two
broad singlets at δ = 3.08 and 3.22 ppm when a glycosyl tri-
choloracetimidate was added to it in the presence of AuCl3.
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in part AuCl3 directly activates the trichloroacetimidate and in
part the phenylacetylene complex activates the trichloroacet-
imidate by the mechanism we proposed. It is clear that there is
participation by and activation of phenylacetylene during the
reaction, which leads to the catalytic cycle, at least in part. The
authors thank one of the referees for advising us to carry out
these experiments.
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Received: January 28, 2015
Published Online: May 8, 2015
Eur. J. Org. Chem. 2015, 4000–4005
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