Gold(III)-Catalyzed Glycosylation using Phenylpropiolate Glycosides: Phenylpropiolic Acid, An Easily Separable and Reusable Leaving Group

Article abstract of DOI:10.1021/acs.joc.8b02422

An efficient and operationally simple gold(III)-catalyzed glycosylation protocol was developed using newly synthesized benchtop stable phenylpropiolate glycosyl (PPG) donors. Gold(III)-catalyzed activation of PPGs proceeds well with various carbohydrate a

Full text of DOI:10.1021/acs.joc.8b02422

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Article
Gold(III)-Catalyzed Glycosylation using Phenylpropiolate Glycosides (PPGs):
Phenylpropiolic Acid An Easily Separable and Reusable Leaving Group
Mukta Shaw, Rima Thakur, and Amit Kumar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02422 • Publication Date (Web): 20 Dec 2018
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Gold(III)-Catalyzed
Glycosylation
using
Phenylpropiolate Glycosides (PPGs): Phenylpropiolic
Acid An Easily Separable and Reusable Leaving
Group
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,‡
,†
Mukta Shaw, Rima Thakur,* and Amit Kumar*
†
Department of Chemistry, Indian Institute of Technology Patna, Bihta 801106, Bihar, India, and
Department of Chemistry, National Institute of Technology Patna, Patna 800005, Bihar, India
‡
ABSTRACT: An efficient and operationally simple gold(III)-catalyzed glycosylation protocol
has been developed using newly synthesized benchtop stable phenylpropiolate glycosyl (PPG)
donors. Gold(III)-catalyzed activation of PPGs proceeds well with various carbohydrate and non-
carbohydrate based glycosyl acceptors and lead to their corresponding O/N-glycosides in good to
excellent yields with regeneration of reusable and easily separable phenylpropiolic acid.
Differentially protected PPGs reacted well under the optimized reaction conditions. In particular,
good anomeric selectivity was observed with mannosyl and rhamnosyl PPG donors. A
preliminary mechanistic study reveals that the presence of triple bond adjacent to the ester group
is essential for the activation and PPG based donor shows higher reactivity than analogous
acetate and benzoate donors.
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
INTRODUCTION
Carbohydrates are the most fundamental and abundant biomolecules present in the living system
that play an important role in controlling the various biological processes, in particular at the cell
surface for instance, cell-cell communication, cellular recognition, cell differentiation, etc. via
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the interaction of carbohydrate moiety with other biomolecules. Besides their role in
metabolism and as a structural source, carbohydrates are an indispensable source of new drugs
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and novel therapeutics. Although nature extensively synthesizes oligosaccharides and
glycoconjugates, it is their intrinsic heterogeneous nature which makes the quantitative isolation
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a formidably challenging task. Therefore, chemical synthesis opens an alternate door for
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obtaining these precious complex compounds in the desired quantity. Fully or partially
protected saccharides bearing leaving group at the anomeric position - glycosyl donor – play a
very important role in chemical glycosylation reactions. Some of the well-known glycosyl
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a,b
5c-e
5f
5g,h
donors include glycosyl trichloroacetimidates, thioglycosides, glycals, glycosyl halides
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and others. Nevertheless, these popular glycosyl donors frequently encounter drawbacks like
low donor stability, require an equimolar amount of promoters, expensive and toxic metal
catalysts, use of hazardous and foul-smelling reagents. In this regard, development of benchtop
stable and efficient glycosyl donors bearing leaving group that may be rapidly introduced and
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can undergo effective glycosylation has been of significant interest to glycochemists. Although
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acetate-based glycosyl donor was first introduced by Helferich et al. in 1933 , this class of donor
has not found extensive application owing to their high stability and requirement of the super-
stoichiometric amount of promoter under harsh reaction conditions. To overcome these issues, in
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990 Kunz et al. has introduced bifunctional leaving group, for instance, glucosyl-4-pentenoates
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as glycosyl donor which could be easily activated under electrophilic conditions. However, the
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major breakthrough was achieved in 2008 by Yu group with the innovation of novel ortho-
alkynylbenzoate as a bifunctional glycosyl donor to synthesize glycosides using gold(I) catalyst
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(Scheme 1a). Afterward, Hotha and coworkers reported an elegant method for glycosylation
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using remote alkynyl carbonate glycoside as stable bifunctional glycosyl donor (Scheme 1b).
Very recently, Zhang et al. have disclosed glycosyl ynenoates as a very effective and stable
bifunctional glycosyl donor, which could be activated under mild conditions using silver (I) salt
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as catalyst. Unfortunately, the major disadvantages of these bifunctional ester based glycosyl
donors are: (i) requirement of additional steps to get the desired coupling partners, (ii) the
formation of lipophilic-byproducts (3, 5 and 7, Scheme 1) in a stoichiometric amount eventually
increasing the challenge for purification of final products, and thus making it unsuitable for
large-scale syntheses and industrial applications. In the view of these fundamental constraints,
recently Jensen et al. have utilized the reusable glycosyl donor such as, ortho-methoxybenzoate
for the glycosylation reactions, where the leaving group could be ideally recycled and reused
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after the reactions.
Therefore, in the field of glycochemistry, it is a continuous demand to develop an efficient and
versatile glycosyl donor, which can be directly prepared in one-step and may regenerate an easily
separable and reusable leaving group. Guided by these facts, we anticipated that the bifunctional
phenylpropiolate glycosides (PPG) 8 obtained via the coupling of lactols and commercially
available phenylpropiolic acid could ideally serve as a stable and efficient glycosyl donor. The
alkyne group present adjacent to the ester moiety in PPG could facilitate the site-control
activation with soft Lewis acid, and that would result in a breaking of anomeric C-1-O-1 bond
with the sole regeneration of phenylpropiolic acid and oxocarbenium ion. Further, the
hydrophilic phenylpropiolic acid may be easily separated from the lipophilic product by simple
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work-up procedure and eventually ease the purification process and could be potentially
exploited for the large-scale synthesis.
Scheme 1. Bifunctional ester based glycosyl donors and their glycosidation
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RESULTS AND DISCUSSION
With this understanding, a series of propiolate based glycosyl donors 12a-c and 13a-h were
synthesized easily by coupling of various glycosyl hemiacetals (10a-h) and acids (e.g., propiolic
acid, 2-hexynoic acid, 2-butynoic acid, and phenylpropiolic acid) under Steglich esterification
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conditions (Scheme 2). The α:β ratios were estimated by H NMR analysis of isolated products.
All the synthesized PPG donors are stable at room temperature for months without any
decomposition. Easy accessibility and high stability of phenylpropiolate glycosides and our own
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research interest in the development of a new synthetic route for glycoside bond formation,
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encouraged us to employ them for glycosylation reaction. Herein, we disclose our detailed
studies with phenylpropiolate glycosides (PPGs) as an effective glycosyl donor.
Scheme 2. Synthesis of phenylpropiolate glycosyl (PPGs) donors
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At the outset, a series of experiments were performed to optimize the reaction conditions using
2,3,4,6-tetra-O-benzyl-α/β-glucosyl phenylpropiolate 13a as model glycosyl donor and
isopropanol as model glycosyl acceptor with gold salt as the choice of catalyst, due to its high
alkynophilicity and mild Lewis acid nature (table 1). Screening with different gold catalysts such
as Au(PPh )Cl, AuCl , AuBr at room temperature in dry CH Cl failed to generate the
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corresponding glycosyl adduct, and a complex reaction mixture was observed on TLC plate
under these conditions (entry 1-3). Interestingly, increasing the reaction temperature to 45 °C in
the presence of 10 mol % of AuCl afforded the desired glycoside 14a in 92% isolated yield with
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expected selectivity (α:β 1:1.3) (entry 4). Addition of additive had no apparent impact on the
reaction outcome (entry 5). A further decrease in the loading of the catalyst from 10 mol % to 5
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mol % was futile, wherein the yield of the desired product decreased up to 68% (entry 6).
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Moreover, nature of the solvent plays a very critical role in the glycosylation reactions. On
identifying the suitable catalyst, the solvent was varied from CH Cl to MeCN, DCE, and THF
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(entry 7-9) to improve the overall yield and selectivity of the product. However, we observed
that none of these solvents gave better yield than CH Cl (entry 4). A control experiment in the
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absence of gold salt yielded no product, and starting material remained intact (entry 10). Further,
the glycosylation reaction was carried out in the inverse addition conditions; a solution of PPG
donor was added to a previously stirred solution of acceptor and catalyst. However, there was no
noteworthy effect on the yield and selectivity of produced glycoside (entry 11). Aware of the fact
that hydrogen chloride (HCl), which is eventually generated in situ from the reaction of AuCl3
and glycosyl acceptor, might be the real catalyst for the activation of PPG donor. Therefore, we
conducted an additional experiment with 10 mol % of HCl in dioxane under similar reaction
conditions (entry 12). Nevertheless, no desired product was observed even after 24 h (TLC
analysis), and the PPG donor was completely intact (recovered through the column
chromatography). From the above result, it appears that HCl did not have any role in this
glycosylation reaction. Additionally, glycosylation reaction was further performed with 10 mol
%
of HAuCl . As expected, the desired product was obtained in 70% yield with moderate
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selectivity along with some hydrolyzed product (entry 13). Further, different metal salts were
also investigated as a catalyst (entry 14-19), and among them, Bi(OTf) Sn(OTf) and FeCl
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provided the corresponding glycoside 14a in optimum yield, albeit under prolonged reaction
time (12-24 h, entries 14, 16 and 19). Indeed, when the reaction was performed with Bronsted
acid (TfOH, entry 20) glycosyl donor 13a did not react at all even after stirring for 24 h.
Furthermore, when the glycosylation reaction was performed with donors, 12a-c under
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established reaction conditions afforded the glycoside 14a in somewhat lower yield (entry 21-
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3). After careful optimization of all reaction parameters, the donor 13a and reaction conditions
described in entry 4, Table 1, were selected as the standard conditions for further exploration.
The merits of this developed glycosyl donors are: (i) direct synthesis of PPGs donor from the
lactol under mild conditions, (ii) formation of hydrophilic phenylpropiolic acid as a reusable by-
product, which can be easily separated from the reaction mixture, (iii) benchtop stable nature of
glycosyl donor, and (iv) additive free glycosylation conditions.
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Table1. Optimization of the reaction conditions
°
b
c
entry
catalyst
temp ( C)
solvent time (h) yield
α/β ratio
d
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Au(PPh )Cl
rt
rt
rt
CH Cl2
24
24
24
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3
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24
16
12
24
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1.5
n.d.d
-
-
-
3
2
AuCl3
AuBr3
AuCl3
CH Cl2
n.d.
n.d.
2
d
CH Cl2
2
45
45
45
65
45
45
45
45
45
45
45
45
45
45
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45
45
45
CH Cl2
92%
88%
68%
54%
30%
trace
1:1.3
1:1
1:1
1:1.5
1:1
-
2
e
AuCl3f
CH Cl2
2
AuCl3
AuCl3
AuCl3
AuCl3
-
CH Cl2
2
MeCN
DCE
THF
g
10
CH Cl2
n.r.
-
2
h
11
12
AuCl
HCl
CH Cl2
83%g
1.2:1
-
1.3:1
1.5:1
-
3
2
i
CH Cl2
n.r.
2
1
1
1
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HAuCl4
Bi(OTf)3
Cu(OTf)2
Sn(OTf)2
AgOTf
CH Cl2
70%
62%
2
CH Cl2
2
g
CH Cl2
n.r.
2
CH Cl2
73%
1.7:1
-
2
g
CH Cl2
n.r.
n.r.
2
g
18
19
Yb(OTf)3
FeCl3
CH Cl2
-
2
CH Cl2
58%
1:1.1
-
1.4:1
2
g
2
2
0
1
TfOHj
CH Cl2
n.r.
2
AuCl3
CH Cl2
70%
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k
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AuCl3l
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45
CH Cl2
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69%
78%
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2:1
2
AuCl3
CH Cl2
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a
Reaction conditions: 13a (0.15 mmol), isopropanol (0.18 mmol), catalyst (10 mol %), 4 Å
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molecular sieves, solvent (3 mL) under nitrogen atmosphere. Yield of the isolated product.
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Anomeric ratio was determined by H NMR spectroscopy. n.d. - not determined. 10 mol % of
f
g
AgOTf was used. 5 mol % of AuCl was used. n.r.- no reaction, starting material was intact.
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j
k
Inverse addition condition. HCl in dioxane was used. 12a was used as glycosyl donor. 12b
l
was used as glycosyl donor. 12c was used as glycosyl donor.
Having optimal reaction conditions in hand, we then turned our attention to explore the scope of
the phenylpropiolate glucosyl donor 13a with various acceptors and results are tabulated in
Scheme 3. Glycosylation of perbenzylated glucopyranosyl phenylpropiolate 13a with halogen-
containing primary alcohols such as 2-bromoethanol, 3-chloropropanol proceeded smoothly to
give glycosides 14b and 14c in 91% and 86% yields respectively, with moderate α-selectivity.
Reaction with bulky primary alcohol, for instance, 1-adamantanemethanol gave the
corresponding glycoside 14d in 97% yield. Off note, when the reaction was carried out with
TMSN under similar conditions, the glycosyl donor 13a afforded the azidoglucoside 14e in
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good yield (84%, α:β 1.8:1). Notably, on reaction with N-hydroxyphthalimide as acceptor also
gave the corresponding glucoside 14f in 78% yield. Similarly, other bulky acceptors such as 1-
adamantanol, cholesterol reacted well to give 14g and 14h in reasonably good yields.
Encouraged with these results, phenylpropiolate glucoside 13a was further reacted with sugar-
based acceptors containing 6-OH group and afforded the corresponding disaccharides 14i-k in
high yields with expected selectivity. Similarly, glycosylation with demanding acceptors having
an unprotected hydroxyl group at 2-,3-,4-positions were also fruitful and gave the desired
disaccharides 14l-n in expected yields (up to 73%). However, to our surprise, in the case of 2-
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hydroxy sugar acceptor, complete α-selectivity was observed, which might be contributed by the
steric factor around the hydroxyl group.
Scheme 3. AuCl catalyzed glycosidation with glucosyl phenylpropiolate 13a and various
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acceptors
Having success with perbenzylated glucopyranosyl phenylpropiolate 13a, the scope of other
glycosyl donors (13b-h) were also investigated with various acceptors (Scheme 4).
Glycosylation of perbenzylated galactopyranosyl phenylpropiolate 13b with a variety of glycosyl
acceptors under the optimized reaction conditions gave their corresponding galactosides 15a-f
respectively in good to excellent yields. Indeed, we observed that galactosyl donor 13b reacted
much faster than the glucosyl donor 13a under similar conditions. Noteworthy, nucleophile like
allyl alcohol, which contains an additional alkene moiety, was also compatible under stabilized
reaction conditions. Interestingly, when thioglucopyranoside containing free 6-OH group was
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treated with donor 13b under gold catalysis conditions, the corresponding glycoside 15e was
isolated in good yield (72%, α:β 3.1:1), and there was no evidence of thioglycoside activation,
1
6
which was a primary concern. This result demonstrates the orthogonality aspect of developed
glycosyl donor. In addition, mannopyranosyl phenylpropiolate donor 13c was also reacted
smoothly with different acceptors such as isopropanol, adamantanol, (+)-menthol and acceptor
containing 6-OH group under the optimized reaction conditions to afford the desired mannosides
in good yields with excellent α-selectivity (16a-d).
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Scheme 4. Substrate Scope
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a
Reaction time 2 h
Furthermore, the glycosylation reaction was carried out with the donor containing the
participating group such as 2-O-benzoyl-3,4,6-tri-O-benzyl-α/β-D-glucopyranosyl
phenylpropiolate 13d in the presence of several acceptors. The reaction with challenging
acceptors, for instance, (+)-menthol, and (-)-menthol required longer reaction time to get the
corresponding glucosides 17c and 17d in moderate yields along with some starting materials.
Similarly, the glycosylation was further investigated with 6-O-benzoyl-2,3,4-tri-O-benzyl-α/β-D-
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glucopyranosylphenylpropiolate 13e and 2,3,4-tri-O-benzyl-6-O-(tert-butyldiphenylsilyl)-α/β-D-
glucopyranosyl phenylpropiolate 13f containing bulky -TBDPS protecting group at 6-position.
All the glycosylation reactions proceeded smoothly to provide the desired products (18a-e and
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9a-e) in good yields with marginal -selectivity. Likewise, when the rhamnosyl donor 13g was
subjected to the established reaction conditions, the corresponding rhamnosides 20a, and 20b
were obtained in good yields (up to 86%) with excellent α-selectivity. Unfortunately, the
glycosylation reaction was unsuccessful with disarmed donor tetra-O-benzoylated
phenylpropiolate glucoside 13h and TLC analysis revealed that multiple uncharacterized
products were formed along with some starting material.
In order to understand the mechanistic aspect of the glycosylation reactions of synthesized PPGs
donor, several control experiments were further carried out. Based on the outcome, we believe
that the alkyne moiety plays a critical role in this glycosylation reaction. Thus, a controlled
experiment was set up with 3-phenylpropionate glucosyl donor 13i and 6-OH acceptor under
similar reaction conditions (Scheme 5a). However, only a small amount of desired glycoside 14i
(18% yield) was isolated and rest starting material was recovered through the column
chromatography. This result illustrates the importance of the alkyne group adjacent to the ester
moiety in the PPG donor. Furthermore, we become interested to compare the reactivity pattern
of our developed PPGs donor with other established ester based glycosyl donors (13j-m), for
instance, glycosyl-1-O-acetate 13j, glycosyl-1-O-benzoate 13k, glycosyl-O-o-methoxybenzoate
13l, and propargyl glycoside 13m (Scheme 5b). For example, when glycosyl-1-O-acetate 13j and
glycosyl-1-O-benzoate 13k donors were separately subjected under optimized reaction
conditions, the desired disaccharide 14i was isolated in lower yields (42% and 19% respectively)
along with some uncharacterized products. Indeed, glycosyl-O-o-methoxybenzoate 13l, and
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propargyl glycoside 13m gave only a trace amount of desired product under the reported
conditions. Also, the competitive experiment was carried out with glycosyl phenylpropiolate 13a
1
and glycosyl-1-O-acetate 13j under standard conditions. H NMR of crude reaction mixture
1
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reveals the disappearance of an anomeric proton (H-1) of PPG 13a is much faster compared to
the anomeric proton (H-1) of glycosyl-1-O-acetate 13j (for details, see supporting information,
Figure S1). These results apparently support our hypothesis and demonstrate the clear
advantages of PPGs donor over the other glycosyl donors.
Scheme 5. Control Experiments
entry
donor
13j
13k
13l
time (h)
24
yield
42%
19%
trace
trace
1
2
3
4
24
24
24
13m
Likewise, the reactivity pattern of PPG donor was further understood from the detailed NMR
experiments. For example, glycosyl donor 13a was treated under similar conditions in CD Cl to
2
2
1
13
acquire H NMR and C NMR spectra for crude reaction mixture (Figure 1). The results showed
the disappearance of an anomeric H-1β proton (δ 5.77) of 13a and downfield shift of C-1 (δ 91.6
1
3
and 95.1 ppm to 94.6 and 102.0 ppm, respectively). Further C NMR spectra reveal the
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regeneration of phenylpropiolic acid (peak at δ 154.9 ppm, which corresponds to the carbonyl
carbon of phenylpropiolic acid). These chemical shift values clearly demonstrate the formation
of O-glycoside and regeneration of phenylpropiolic acid in the glycosylation reaction.
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13a
(a)
H-1α H-1β
13a+ isopropanol+ AuCl
3
(b)
C-1β
95.13
13a
C-1α
91.65
(c)
1
3a+ isopropanol+ AuCl
3
C-1β
102.02
(d)
C-1α
4.69
9
(e)
1
Figure 1. H NMR spectra of (a) glycosyl donor 13a, (b) reaction mixture of 13a, isopropanol
13
and 10 mol % of AuCl at 45 °C after 30 min, and C NMR spectra of (c) glycosyl donor 13a
3
(
d) reaction mixture of 13a, isopropanol and 10 mol % of AuCl at 45 °C after 30 min in CD Cl .
3 2 2
1
3
(e) Full C NMR spectra of crude reaction mixture.
Aware of the fact that hydrophilic phenylpropiolic acid is regenerating during the glycosylation
reaction, we became interested in demonstrating the reusability of phenylpropiolic acid. The
reaction of glycosyl donor 13a (200 mg, 0.3 mmol) was carried out with isopropanol under the
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optimal reaction conditions (Scheme 6). The reaction mixture was washed with a saturated
aqueous solution of NaHCO , followed by acidification with 2 (M) HCl solutions to regenerate
3
phenylpropiolic acid in 91% yield. Subsequently, the regenerated phenylpropiolic acid was
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coupled with glucosyl hemiacetal 10a to produce the corresponding PPG donor 13a.
Scheme 6. Regeneration of phenylpropiolic acid
To demonstrate the application of the established donor in complex oligosaccharides synthesis,
we next employed PPG donor for the synthesis of the trisaccharide 21 (Scheme 7). Treatment of
2,3,4,6-tetra-O-benzyl-α/β-D-galactopyranosyl phenylpropiolate 13b with 6-unprotected
acceptor 2,3,4-tri-O-benzoyl-β-D-thioglucoside under the optimized reaction conditions afforded
the disaccharide 15e in 72% yield. Indeed, this result illustrates that PPG 13b is orthogonal to the
thioglycoside under our developed conditions. Further, compound 15e was glycosylated with
1
7
acceptor under previously established reaction condition to give trisaccharide 21 in 65% yield.
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Scheme 7. Application of PPG donor for the synthesis of a trisaccharide
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Based on the aforementioned experimental results and literature precedents, a plausible reaction
mechanism for Au(III) catalyzed activation of phenylpropiolate glycosyl (PPG) donor is given in
Figure 2. At first, mild Lewis acid and alkynophilic AuCl coordinates to both the carbonyl
3
oxygen and alkyne bond of the glycosyl donor 13 to form a gold-alkyne complex A.
Concomitantly, lone pair of electron from the endocyclic oxygen atom facilitates the expulsion
of phenylpropiolate ion C from the complex A and generate the oxocarbenium ion B.
Subsequently, species B react with glycosyl acceptor to give the corresponding glycoside 14 and
release of proton further trapped by species C to regenerate the phenylpropiolic acid.
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Figure 2. Anticipated mechanism for Au(III) catalyzed activation of phenylpropiolate glycosyl
(PPG) donors
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
CONCLUSION
In conclusion, we have designed and developed phenylpropiolate glycosides (PPGs) as stable
and effective glycosyl donor, which could be activated with gold(III) salt under mild conditions.
Phenylpropiolate glycosyl (PPG) donors were reacted with a wide range of sugar and nonsugar
acceptors to produce desired glycosides in good to excellent yields with expected selectivity.
Some of the noteworthy features of the developed donors are a) formation of hydrophilic
phenylpropiolic acid as reusable and easily separable leaving group, b) additive free catalytic
system, c) direct synthesis of glycosyl donors, and d) long shelf life.
EXPERIMENTAL SECTION
General Methods.
All chemicals were purchased as reagent grade and used without further purification unless
otherwise mentioned. Solvents were purified by standard procedures. All reactions were carried
out under a nitrogen atmosphere with freshly distilled solvents unless otherwise mentioned.
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6
Molecular sieves (4 Å) were flame dried before use. Reactions were monitored by analytical
thin-layer chromatography 60 F254 silica gel, precoated on aluminum plates. TLC plates were
visualized by spraying 10% H SO in MeOH and heating until spots appeared or under UV light
2
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(254 nm). Column chromatography was performed using silica gel (100-200 mesh). Optical
rotations were recorded on a digital polarimeter. IR spectra were recorded on an FT-IR
1
13
spectrometer (UATR). H and C NMR spectra were recorded at 400 and 100 MHz respectively.
Chemical shifts (δ) are reported in parts per million (ppm) relative to tetramethylsilane or solvent
1
13
1
residual signals ( H NMR: solvent CDCl , δ = 7.26 ppm; CD Cl , δ = 5.30 ppm; C{ H} NMR:
3
2
2
solvent CDCl , δ = 77.22 ppm; CD Cl , δ = 54.00 ppm). HRMS spectra were recorded on an
3
2
2
ESI-mass spectrometer (Q-TOF, positive ion).
Experimental Procedures. General procedure for the synthesis glycosyl donors (A): An
oven dried round bottom flask was charged with glycosyl hemiacetal (1.0 mmol) and acid
coupling partner (propiolic acid or phenyl propiolic acid) (1.5 mmol) in dry CH Cl (5 mL), and
2
2
the mixture was stirred at 0 °C for 30 minutes. A solution containing the mixture of DCC (1.5
mmol) and DMAP (0.2 mmol) in dry CH Cl (5 mL), was added to the reaction solution at 0 °C
2
2
and the reaction mixture was bring to room temperature. The reaction mixture was stirred at
room temperature until the completion of the reaction, monitored by TLC. After completion, the
reaction mixture was diluted with CH Cl and filtered through a pad of celite. The filtrate was
2
2
concentrated in vacuo and purified by column chromatography (ethyl acetate-hexanes gradient
elution) to afford the corresponding glycosyl donors.
2,3,4,6-Tetra-O-benzyl-α/β-D-glucopyranosyl propiolate (12a). The compound 12a was obtained
from the reaction between 2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranose (540.6 mg, 0.6 mmol, 1.0
equiv) and propiolic acid (52 µL, 0.8 mmol, 1.5 equiv) following the general procedure A as
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pale yellow liquid (151 mg, 46%, α/β 1:1.3). R : 0.35 (ethyl acetate/hexane 1:10 (v/v) , [α] = +
f
D
-1
1
3
6.7 (c = 0.2, CH Cl ); IR (cm , CH Cl ): 3036, 2928, 2126, 1731, 1453, 1264, 1217; H NMR
2 2 2 2
(400 MHz, CDCl ) δ 7.30 – 7.12 (m, 37.1H), 7.10 – 7.00 (m, 4.3H), 6.29 (d, J = 3.0 Hz, 0.8H),
3
1
1
1
1
1
1
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.57 (d, J = 7.8 Hz, 1.0H), 4.92 – 4.64 (m, 8.6H), 4.63 – 4.34 (m, 8.4H), 3.93 – 3.79 (m, 1.9H),
13
1
3
.71 – 3.47 (m, 10.7H), 2.90 (s, 0.8H), 2.86 (s, 0.7H); C{ H} NMR (100 MHz, CDCl ) δ 151.1,
3
1
51.0, 138.6, 138.3, 138.0, 137.9, 137.8, 137.5, 128.6, 128.5, 128.4, 128.2, 128.0, 127.9, 127.8,
27.7, 95.3, 92.0, 84.6, 81.5, 80.6, 78.7, 76.7, 76.2, 75.9, 75.8, 75.3, 75.2, 75.1, 74.3, 74.2, 73.6,
1
+
7
3.5, 73.3, 68.1, 67.9; HRMS (ESI/Q-TOF) m/z: [M + Na] Calcd for C H O Na 615.2353;
37
36
7
Found 615.2345.
2
,3,4,6-Tetra-O-benzyl-α/β-D-glucopyranosyl 2-hexynoate (12b). The compound 12b was
obtained from the reaction between 2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranose (1081.3 mg, 0.9
mmol, 1.0 equiv) and 2-hexynoic acid (157.0 µL, 1.4 mmol, 1.5 equiv) following the general
procedure A as pale yellow liquid (328 mg, 57%, α/β 1.2:1). R : 0.39 (ethyl acetate/hexane 1:10
f
28
-1
(v/v) ), [α]D = + 48.5 (c = 0.26, CH Cl ); IR (cm , CH Cl ): 3063, 3030, 2963, 2933, 2873,
2
2
2
2
1
2
233, 2116, 1716, 1453, 1360, 1240, 1153; H NMR (400 MHz, CDCl ) δ 7.40 – 7.24 (m,
3
3
4.7H), 7.17 – 7.13 (m, 3.9H), 6.37 (d, J = 3.5 Hz, 1.0H), 5.66 (d, J = 8.0 Hz, 0.8H), 4.99 (d, J =
10.9 Hz, 1.1H), 4.94 – 4.60 (m, 11.2H), 4.57 – 4.44 (m, 4.1H), 4.05 – 3.90 (m, 2.3H), 3.80 – 3.56
1
3
1
(
m, 10.8H), 2.37 – 2.29 (m, 4.7H), 1.68– 1.61 (m, 7.1H), 1.03 (t, J = 7.4 Hz, 7.3H); C{ H}
NMR (100 MHz, CDCl ) δ 152.2, 152.0, 138.7, 138.4, 138.0, 137.9, 137.8, 137.6, 128.5, 128.4,
3
128.3, 128.2, 128.1, 128.0, 127.9, 95.0, 91.9, 91.3, 84.6, 81.6, 80.8, 78.8, 77.2, 76.9, 75.8, 75.7,
7
5.3, 75.1, 73.6, 73.5, 73.3, 73.0, 72.9, 68.2, 68.0, 21.0, 20.8, 20.7, 13.6, 13.5; HRMS (ESI/Q-
+
TOF) m/z: [M + Na] Calcd for C H O Na 657.2823; Found 657.2829.
4
0
42
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2
,3,4,6-Tetra-O-benzyl-α/β-D-glucopyranosyl 2-butynoate (12c). The compound 12c was
obtained from the reaction between 2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranose (400.0 mg, 0.7
mmol, 1.0 equiv) and 2-butynoic acid (93.0 µL, 1.1 mmol, 1.5 equiv) following the general
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0
procedure A as colourless liquid (298 mg, 66%, α/β 1.8:1). R : 0.37 (ethyl acetate/hexane 1:10
f
28
-1
(v/v) ), [α]D = + 38.4 (c = 0.20, CH Cl ); IR (cm , CH Cl ): 3064, 3030, 2925, 2868, 2243,
2 2 2 2
1
1
7
1
3
719, 1496, 1452, 1358, 1246; H NMR (400 MHz, CDCl ) δ 7.37 – 7.27 (m, 26.4H), 7.16 –
3
.13 (m, 2.9H), 6.35 (d, J = 3.4 Hz, 1.0H), 5.66 (d, J = 8.0 Hz, 0.5H), 4.98 (d, J = 10.9 Hz,
.0H), 4.91 – 4.80 (m, 4.4H), 4.78 – 4.72 (m, 0.9H), 4.70 – 4.58 (m, 3.4H), 4.57 – 4.46 (m,
.3H), 4.00 (t, J = 9.3 Hz, 1.1H), 3.93 (d, J = 10.0 Hz, 1.1H), 3.79 – 3.56 (m, 7.8H), 2.02 (s,
13
1
1.5H), 2.00 (s, 3.0H); C{ H} NMR (100 MHz, CDCl ) δ 152.1, 152.0, 138.7, 138.4, 138.1,
3
1
8
38.0, 137.9, 137.8, 137.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.5, 95.0, 91.3,
7.8, 87.3, 84.6, 81.6, 80.8, 78.7, 77.2, 76.8, 75.8, 75.7, 75.3, 75.1, 75.0, 73.6, 73.3, 73.1, 72.2,
+
72.0, 68.2, 68.0, 3.9; HRMS (ESI/Q-TOF) m/z: [M + Na] Calcd for C H O Na 629.2510;
38
38
7
Found 629.2496.
2
,3,4,6-Tetra-O-benzyl-α/β-D-glucopyranosyl phenylpropiolate (13a). The compound 13a was
obtained from the reaction between 2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranose (1081.3 mg, 2.0
mmol, 1.0 equiv) and phenylpropiolic acid (438.4 mg, 3.0 mmol, 1.5 equiv) following the
general procedure A as pale yellow liquid (1150 mg, 86%, α/β 2.3:1). R : 0.37 (ethyl
f
28
-1
acetate/hexane 1:10 (v/v) ), [α]D = + 41.5 (c = 0.2, CH Cl ); IR (cm , CH Cl ): 3033, 2923,
2
2
2
2
1
2870, 2213, 1716, 1360, 1283; H NMR (400 MHz, CDCl ) δ 7.76 – 7.67 (m, 2.9H), 7.53 (dd, J
3
=
6.8, 4.9 Hz, 1.6H), 7.50 – 7.31 (m, 29.7H), 7.28 – 7.20 (m, 3.2H), 6.55 (d, J = 3.2 Hz, 1.0H),
5
.85 (d, J = 7.8 Hz, 0.4H), 5.10 (d, J = 10.9 Hz, 1.0H), 5.05 – 4.86 (m, 4.6H), 4.84 – 4.67 (m,
.4H), 4.66 – 4.55 (m, 2.7H), 4.20 – 4.07 (m, 2.0H), 3.96 – 3.81 (m, 4.9H), 3.80 – 3.70 (m,
3
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13
1
1
1
.9H); C{ H} NMR (100 MHz, CDCl ) δ 152.5, 152.3, 138.7, 138.4, 138.0, 137.9, 137.8,
3
37.5, 133.2, 131.0, 130.9, 128.7, 128.6, 128.5, 128.4, 128.2, 128.0, 127.9, 127.8, 127.7, 119.5,
119.3, 95.1, 91.6, 88.4, 87.9, 84.7, 81.6, 80.8, 80.3, 80.2, 78.8, 75.8, 75.4, 75.2, 75.1, 73.6, 73.4,
+
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
6
3.2, 68.1, 68.0; HRMS (ESI/Q-TOF) m/z: [M + Na] Calcd for C H O Na 691.2672; Found
4
3
40
7
91.2686.
2
,3,4,6-Tetra-O-benzyl-α/β-D-galactopyranosyl phenylpropiolate (13b). The compound 13b was
obtained from the reaction between 2,3,4,6-tetra-O-benzyl-α/β-D-galactopyranose (540.65 mg,
.0 mmol, 1.0 equiv) and phenylpropiolic acid (219.2 mg, 1.5 mmol, 1.5 equiv) following the
general procedure A as pale yellow liquid (588 mg, 88%, α/β 2.2:1). R : 0.37 (ethyl
1
f
28
-1
acetate/hexane 1:10 (v/v), [α]D = +48.13 (c = 0.3, CH Cl ); IR (cm , CH Cl ): 3036, 2923,
2
2
2
2
1
2
7
873, 2216, 1713, 1456, 1356, 1280; H NMR (400 MHz, CDCl ) δ 7.66 (d, J = 6.7 Hz, 3.5H),
3
.55 – 7.26 (m, 38.7H), 6.53 (d, J = 3.2 Hz, 1.0H), 5.77 (d, J = 7.5 Hz, 0.4H), 5.02 (d, J = 10.8
Hz, 1.6H), 4.93 – 4.73 (m, 6.5H), 4.72 – 4.42 (m, 6.1H), 4.32 – 4.02 (m, 6.1H), 3.94 – 3.56 (m,
1
3
1
4.8H); C{ H} NMR (100 MHz, CDCl ) δ 152.7, 152.4, 138.7, 138.5, 138.2, 138.0, 137.8,
3
1
9
33.1, 130.8, 128.6, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.6, 127.5, 127.4, 119.6, 95.4,
2.6, 87.6, 82.3, 80.6, 78.7, 78.0, 75.5, 75.3, 75.0, 74.6, 73.6, 73.2, 73.0, 72.2, 68.3, 68.0; HRMS
+
(ESI/Q-TOF) m/z: [M + Na] Calcd for C H O Na 691.2672; Found 691.2674.
4
3
40
7
2,3,4,6-Tetra-O-benzyl-α/β-D-mannopyranosyl phenylpropiolate (13c). The compound 13c was
obtained from the reaction between 2,3,4,6-tetra-O-benzyl-α/β-D-mannopyranose (1024 mg, 1.9
mmol, 1.0 equiv) and phenylpropiolic acid (415 mg, 2.8 mmol, 1.5 equiv) following the general
procedure A as pale yellow liquid (1102.0 mg, 87%, α/β 3.7:1). R : 0.37 (ethyl acetate/hexane
f
28
-1
1
:10 (v/v) ), [α]D = -13.72 (c = 0.28, CH Cl ); IR (cm , CH Cl ): 3064, 3032, 2931, 2864,
2 2 2 2
1
2
216, 1718, 1494, 1452, 1362, 1284; H NMR (400 MHz, CDCl ) δ 7.60 (d, J = 7.6 Hz, 3.1H),
3
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7
.48 (t, J = 7.1 Hz, 2.4H), 7.45 – 7.25 (m, 27.5H), 7.22 – 7.14 (m, 3.0H), 6.33 (s, 1.0H), 5.73 (s,
.3H), 4.96 – 4.86 (m, 1.9H), 4.83 – 4.72 (m, 2.2H), 4.70 – 4.54 (m, 7.3H), 4.14 (t, J = 9.6 Hz,
0
1
3
1
1.2H), 4.06 – 3.94 (m, 2.8H), 3.87 – 3.71 (m, 4.1H), 3.68 – 3.59 (m, 0.7H); C{ H} NMR (100
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MHz, CDCl ) δ 152.1, 152.0, 138.2, 137.7, 133.2, 133.1, 132.6, 131.0, 128.7, 128.6, 128.5,
3
1
7
28.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 119.3, 119.2, 94.1, 93.3, 81.9, 80.1,
9.2, 75.3, 75.1, 74.7, 74.2, 74.1, 73.5, 73.3, 73.1, 72.7, 72.3, 72.2, 69.0, 68.8; HRMS (ESI/Q-
+
TOF) m/z: [M + Na] Calcd for C H O Na 691.2672; Found 691.2674.
4
3
40
7
2
-O-Benzoyl-3,4,6-tri-O-benzyl-α/β-D-glucopyranosyl phenylpropiolate (13d). The compound
1
3d was obtained from the reaction between 2-O-benzoyl-3,4,6-tri-O-benzyl-α/β-D-
glucopyranose (554.6 mg, 1.0 mmol, 1.0 equiv) and phenylpropiolic acid (219.2 mg, 1.5 mmol,
1
0
3
.5 equiv) following the general procedure A as pale yellow liquid (532 mg, 78%, α/β 2.2:1). Rf :
28
-1
.3 (ethyl acetate/hexane 1:10 (v/v), [α]D = + 136.8 (c = 0.22, CH Cl ); IR (cm , CH Cl ):
2
2
2
2
1
036, 2923, 2870, 2226, 1723, 1450, 1360, 1260; H NMR (400 MHz, CDCl ) δ 8.07 – 7.86 (m,
3
4.2H), 7.58 – 7.45 (m, 5.3H), 7.42 – 7.19 (m, 23.3H), 7.16 – 7.00 (m, 10.4H), 6.50 (d, J = 3.2
Hz, 1.0H), 5.85 (d, J = 8.1 Hz, 0.4H), 5.41 (t, J = 8.5 Hz, 0.4H), 5.35 – 5.29 (m, 0.7H), 5.22 (s,
0
.7H), 4.89 – 4.68 (m, 4.4H), 4.63 – 4.42 (m, 5.8H), 4.20 (t, J = 7.9 Hz, 1.2H), 4.02 (d, J = 9.2
1
3
1
Hz, 1.1H), 3.90 – 3.61 (m, 5.8H); C{ H} NMR (100 MHz, CDCl ) δ 165.5, 165.1, 152.3,
3
1
1
52.0, 138.0, 137.9, 137.8, 137.5, 133.7, 133.4, 133.3, 133.2, 131.0, 130.2, 130.0, 129.9, 129.8,
29.4, 129.3, 128.7, 128.5, 128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.7, 119.3, 119.2, 93.0,
91.6, 88.2, 82.5, 79.9, 76.2, 75.7, 75.5, 75.2, 75.1, 73.6, 73.5, 72.3, 68.1, 67.9; HRMS (ESI/Q-
+
TOF) m/z: [M + Na] Calcd for C H O Na 705.2459; Found 705.2432.
4
3
38
8
6
-O-Benzoyl-2,3,4-tri-O-benzyl-α/β-D-glucopyranosyl phenylpropiolate (13e). The compound
1
3e was obtained from the reaction between 6-O-benzoyl-2,3,4-tri-O-benzyl-α/β-D-
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glucopyranose (538 mg, 0.97 mmol, 1.0 equiv) and phenylpropiolic acid (214 mg, 1.45 mmol,
1
.5 equiv) following the general procedure A as pale yellow liquid (608 mg, 92%, α/β 2.5:1). Rf :
2
8
-1
0.35 (ethyl acetate/hexane 1:10 (v/v), [α]D = + 30.60 (c = 0.23, CH Cl ); IR (cm , CH Cl ):
2
2
2
2
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
8
2
1
032, 2931, 2860, 2214, 1717, 1450, 1359, 1274; H NMR (400 MHz, CDCl ) δ 8.02 (dd, J =
3
.4, 7.8 Hz, 2.9H), 7.64 (dd, J = 8.3, 1.3 Hz, 2.0H), 7.61 – 7.54 (m, 2.7H), 7.50 – 7.30 (m,
2.0H), 7.30 – 7.22 (m, 8.3H), 6.44 (d, J = 3.5 Hz, 1.0H), 5.80 (d, J = 7.9 Hz, 0.4H), 5.04 (d, J =
0.7 Hz, 1.0H), 4.98 – 4.69 (m, 6.5H), 4.66 – 4.47 (m, 4.8H), 4.22 – 4.10 (m, 2.2H), 3.86 – 3.71
13
1
(
m, 4.2H); C{ H} NMR (100 MHz, CDCl ) δ 166.1, 152.4, 152.1, 138.3, 138.1, 137.7, 137.5,
3
1
37.4, 133.2, 133.1, 130.9, 129.8, 129.7, 128.7, 128.6, 128.4, 128.2, 128.1, 128.0, 119.4, 119.2,
95.0, 91.2, 88.1, 84.7, 81.6, 80.8, 80.3, 79.0, 76.0, 75.5, 75.3, 74.1, 73.5, 71.6, 63.0, 62.8; HRMS
+
(
ESI/Q-TOF) m/z: [M + Na] Calcd for C H O Na 705.2459; Found 705.2445.
4
3
38
8
2
,3,4-Tri-O-benzyl-6-O-(tert-butyldiphenylsilyl)-α/β-D-glucopyranosyl phenylpropiolate (13f).
The compound 13f was obtained from the reaction between 2,3,4-tri-O-benzyl-6-O-(tert-
butyldiphenylsilyl)-α/β-D-glucopyranose (554.6 mg, 1.0 mmol, 1.0 equiv) and phenylpropiolic
acid (219 mg, 1.5 mmol, 1.5 equiv) following the general procedure A as pale yellow liquid
2
8
(
613 mg, 75%, α/β 3.5:1). R : 0.40 (ethyl acetate/hexane 1:10 (v/v), [α]D = + 34.10 (c = 0.26,
f
-1
1
CH Cl ); IR (cm , CH Cl ): 3073, 3030, 2930, 2863, 2220, 1720, 1450, 1360, 1280; H NMR
2
2
2
2
(
400 MHz, CDCl ) δ 7.64 – 7.44 (m, 10.0H), 7.37 – 7.06 (m, 40.3H), 6.39 (d, J = 3.0 Hz, 1.0H),
3
5
.63 (d, J = 7.7 Hz, 0.3H), 5.14 (d, J = 3.9 Hz, 0.4H), 4.94 – 4.72 (m, 4.8H), 4.70 – 4.55 (m,
3.9H), 4.02 – 3.94 (m, 1.1H), 3.92 – 3.77 (m, 5.4H), 3.74 – 3.58 (m, 2.5H), 3.38 (d, J = 9.3 Hz,
1
3
1
0
1
1
.3H), 0.95 (s, 14.1H); C{ H} NMR (100 MHz, CDCl ) δ 152.6, 152.3, 138.6, 138.3, 138.2,
3
38.0, 137.7, 136.0, 135.9, 135.7, 133.6, 133.2, 133.0, 132.7, 130.8, 129.8, 129.7, 128.7, 128.6,
28.5, 128.2, 128.1, 128.0, 127.8, 127.7, 127.6, 119.5, 95.4, 91.7, 87.7, 84.7, 81.7, 81.2, 80.4,
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
8
0.3, 79.4, 76.5, 76.0, 75.5, 75.3, 74.3, 73.6, 62.2, 32.8, 30.8, 26.9, 19.4; HRMS (ESI/Q-TOF)
+
m/z: [M + Na] Calcd for C H O SiNa 839.3375; Found 839.3351.
52
52
7
2
,3,4,-Tri-O-benzyl-α/β-L-rhamnopyranosyl phenylpropiolate (13g). The compound 13g was
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
obtained from the reaction between 2,3,4-tri-O-benzyl-α/β-D-rhamnopyranose (330 mg, 0.8
mmol, 1.0 equiv) and phenylpropiolic acid (166 mg, 1.1 mmol, 1.5 equiv) following the general
procedure A as pale yellow liquid (320 mg, 71%, α/β 2:1). R : 0.35 (ethyl acetate/hexane 1:10
f
28
-1
(v/v) ), [α]D = + 41.5 (c = 0.2, CH Cl ); IR (cm , CH Cl ): 3064, 3029, 2980, 2932, 2867, 2216,
2
2
2
2
1
1
718, 1491, 1452, 1365, 1281; H NMR (400 MHz, CDCl ) δ 7.65 – 7.56 (m, 3.6H), 7.53 – 7.44
3
(m, 3.1H), 7.43 – 7.27 (m, 25.8H), 6.22 (s, 1.0H), 5.68 (s, 0.5H), 5.00 – 4.92 (m, 2.5H), 4.77 (d,
J = 3.0 Hz, 1.9H), 4.69 – 4.56 (m, 4.8H), 4.04 – 3.82 (m, 4.0H), 3.73 – 3.66 (m, 1.7H), 3.59 (dd,
1
3
1
J = 9.3, 2.6 Hz, 0.5H), 3.56 – 3.47 (m, 0.7H), 1.40 (dd, J = 11.5, 6.1 Hz, 4.9H); C{ H} NMR
(100 MHz, CDCl ) δ 152.1, 152.0, 138.3, 138.2, 138.1, 138.0, 137.7, 133.2, 133.1, 132.7, 131.0,
3
1
28.7, 128.6, 128.5, 128.4, 128.3, 128.1, 127.9, 127.8, 127.7, 127.6, 119.3, 119.2, 94.0, 93.3,
88.2, 87.7, 82.1, 80.1, 79.8, 79.6, 79.2, 75.6, 75.5, 74.3, 73.5, 73.3, 73.1, 72.8, 72.3, 72.2, 70.9,
+
1
8.1, 17.9; HRMS (ESI/Q-TOF) m/z: [M + Na] Calcd for C H O Na 585.2248; Found
3
6
34
6
5
85.2258.
2
,3,4,6-Tetra-O-benzoyl-α/β-D-glucopyranosyl phenylpropiolate (13h). The compound 13h was
obtained from the reaction between 2,3,4,6-tetra-O-benzoyl-α/β-D-glucopyranose (596.5 mg, 1.0
mmol, 1.0 equiv) and phenylpropiolic acid (220.0 mg, 1.5 mmol, 1.5 equiv) following the
general procedure A as yellow solid (595 mg, 82%, α/β 3:1). R : 0.30 (ethyl acetate/hexane 1:4
f
2
8
-1
(v/v) , [α]D = + 15.6 (c = 0.25, CH Cl ); IR (cm , CH Cl ): 3068, 2961, 2215, 1728, 1602,
2
2
2
2
1
1
450, 1261; H NMR (400 MHz, CDCl ) δ 8.06 (d, J = 7.3 Hz, 2.9H), 7.99 – 7.93 (m, 4.8H),
3
7
.88 (d, J = 7.5 Hz, 2.7H), 7.71 (d, J = 7.2 Hz, 2.0H), 7.57 – 7.50 (m, 5.2H), 7.43 (dd, J = 10.2,
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.5 Hz, 7.0H), 7.40 – 7.30 (m, 9.3H), 6.75 (d, J = 3.7 Hz, 1.0H), 6.30 – 6.23 (m, 1.3H), 5.96 (t, J
=
9.4 Hz, 0.4H), 5.86 – 5.73 (m, 1.8H), 5.62 (dd, J = 10.3, 3.7 Hz, 1.0H), 4.69 – 4.63 (m, 2.1H),
1
3
1
4.54 – 4.46 (m, 1.6H), 4.40 – 4.33 (m, 0.4H); C{ H} NMR (100 MHz, CDCl ) δ 166.1, 165.8,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
7
65.6, 165.4, 165.1, 164.9, 151.8, 151.7, 133.6, 133.5, 133.4, 133.3, 133.2, 131.2, 131.1, 130.0,
29.9, 129.8, 129.6, 129.5, 128.9, 128.7, 128.6, 128.5, 128.4, 128.3, 119.1, 92.8, 90.7, 89.4, 89.2,
+
9.7, 73.4, 72.8, 70.7, 70.6, 70.2, 68.9, 68.7, 62.7, 62.4; HRMS (ESI/Q-TOF) m/z: [M + Na]
Calcd for C H O Na 747.1837; Found 747.1842.
4
3
32 11
2
,3,4,6-Tetra-O-benzyl-α/β-D-glucopyranosyl-3-phenylpropionate (13i). The compound 13i was
obtained from the reaction between 2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranose (596.5 mg, 1.0
mmol, 1.0 equiv) and 3-phenylpropionic acid (220.0 mg, 1.5 mmol, 1.5 equiv) following the
general procedure A as colourless liquid (595 mg, 82%, α/β 3:1). R : 0.32 (ethyl acetate/hexane
f
28
1
1
:10 (v/v) , [α]D = + 28.3 (c = 0.21, CH Cl ). H NMR (400 MHz, CDCl ) δ 7.43 – 7.17 (m,
2 2 3
3
6.1H), 6.42 (d, J = 3.4 Hz, 1.0H), 5.69 (d, J = 8.1 Hz, 0.3H), 5.02 – 4.48 (m, 12.3H), 3.94 (t, J =
8.7 Hz, 1.1H), 3.85 – 3.70 (m, 5.9H), 3.63 (t, J = 8.7 Hz, 1.9H), 3.04 – 2.95 (m, 2.9H), 2.83 –
13
1
2
.55 (m, 3.1H); C{ H} NMR (100 MHz, CDCl ) δ 171.4, 171.3, 140.2, 138.7, 138.4, 138.1,
3
1
37.9, 137.8, 137.7, 128.6, 128.5, 128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 126.4,
126.3, 94.2, 90.1, 84.8, 81.6, 78.9, 75.7, 75.6, 75.3, 75.0, 73.6, 73.2, 72.9, 68.1, 35.8, 35.8, 30.8,
+
3
0.5; HRMS (ESI/Q-TOF) m/z: [M + Na] Calcd for C H O Na 695.2979; Found 695.2985.
4
3
44
7
9e
2
,3,4,6-Tetra-O-benzyl-1-O-acetyl-α/β-D-glucopyranose (13j).
The compound 13j was
synthesized using literature reported procedure and obtained as colourless liquid (288 mg, 90%,
1
α/β 3.2:1). R : 0.42 (ethyl acetate/hexane 1:4 (v/v). H NMR (400 MHz, CDCl ) δ 7.37 – 7.27
f
3
(m, 22.9H), 7.18 – 7.13 (m, 2.7H), 6.36 (d, J = 3.5 Hz, 1.0H), 5.61 (d, J = 8.1 Hz, 0.3H), 4.97 (d,
J = 10.9 Hz, 1.0H), 4.89 – 4.75 (m, 3.7H), 4.73 – 4.59 (m, 3.5H), 4.50 (t, J = 10.6 Hz, 2.9H),
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.94 (d, J = 9.3 Hz, 1.1H), 3.87 (d, J = 9.9 Hz, 1.1H), 3.77 – 3.55 (m, 6.4H), 2.14 (s, 3.0H), 2.06
1
3
1
(s, 0.9H); C{ H} NMR (100 MHz, CDCl ) δ 169.4, 169.3, 138.7, 138.4, 138.1, 137.9, 137.6,
3
128.5, 128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 94.1, 90.0, 84.8, 81.7, 81.1, 78.9,
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0
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8
9
0
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8
9
0
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5.7, 75.5, 75.3, 75.0, 73.6, 73.2, 72.9, 68.2, 21.1, 21.0.
18
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,3,4,6-Tetra-O-benzyl-1-O-benzoyl-α/β-D-glucopyranose (13k). The compound 13k was
synthesized using literature reported procedure and obtained as colourless liquid (356 mg, 75%,
1
α/β 1:8.1). R : 0.4 (ethyl acetate/hexane 1:7 (v/v). H NMR (400 MHz, CDCl ) δ 8.16 – 8.06 (m,
f
3
3
.7H), 7.64 – 7.58 (m, 1.7H), 7.51 – 7.44 (m, 3.9H), 7.35 – 7.26 (m, 16.0H), 7.21 (s, 4.2H), 7.16
(dd, J = 7.1, 2.4 Hz, 2.4H), 6.62 (d, J = 3.5 Hz, 0.1H), 5.90 (dd, J = 5.7, 2.0 Hz, 1.0H), 4.96 –
1
3
1
4
.73 (m, 6.4H), 4.65 – 7.47 (m, 4.1H), 3.87 – 3.73 (m, 6.2H), 3.71 – 3.64 (m, 1.4H); C{ H}
NMR (100 MHz, CDCl ) δ 164.9, 138.4, 138.1, 137.9, 137.8, 133.7, 133.6, 130.2, 130.1, 129.3,
3
1
7
28.5, 128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.7, 94.7, 84.9, 80.9, 75.7, 75.6, 75.1, 75.0,
3.5, 68.1.
1
3d
2,3,4,6-Tetra-O-benzyl-1-O-(o-methoxybenzoyl)-α/β-D-glucopyranose (13l).
The compound
1
3l was obtained from the reaction between 2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranose (596.5
mg, 1.0 mmol, 1.0 equiv) and 2-methoxybenzoic acid (220.0 mg, 1.5 mmol, 1.5 equiv) following
the general procedure A as colourless liquid (595 mg, 82%, α/β 3:1). R : 0.30 (ethyl
f
1
acetate/hexane 1:10 (v/v). H NMR (400 MHz, CDCl ) δ 7.88 (ddd, J = 5.9, 3.9, 1.4 Hz, 2.1H),
3
7
.55 – 7.47 (m, 2.8H), 7.39 – 7.22 (m, 41.5H), 7.21 – 7.16 (m, 4.2H), 7.03 – 6.92 (m, 5.5H), 6.62
d, J = 3.4 Hz, 1.0H), 5.89 (d, J = 7.6 Hz, 0.8H), 5.00 – 4.75 (m, 10.4H), 4.71 – 4.46 (m, 8.7H),
4.09 – 3.99 (m, 2.4H), 3.89 (d, J = 4.0 Hz, 8.9H), 3.84 – 3.73 (m, 8.9H), 3.71 – 3.64 (m, 2.5H);
(
1
3
1
C{ H} NMR (100 MHz, CDCl ) δ 164.4, 164.0, 159.9, 159.7, 138.7, 138.5, 138.3, 138.1,
3
1
38.0, 137.9, 137.8, 134.3, 134.1, 132.3, 132.2, 130.7, 128.4, 128.3, 128.1, 128.0, 127.9, 127.8,
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27.7, 127.6, 121.1, 120.2, 112.1, 111.0, 94.4, 90.3, 84.9, 81.8, 81.1, 79.0, 75.6, 75.2, 75.0, 74.9,
3.6, 73.5, 73.1, 72.9, 68.2, 55.8, 55.7.
1
1a
Propargyl 2,3,4,6-tetra-O-benzyl-α/β-glucopyranoside (13m).
The compound 13m was
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0
synthesized using literature reported procedure and obtained as pale yellow solid (520 mg, 82%,
1
α/β 3.2.1). R : 0.37 (ethyl acetate/hexane 1:10 (v/v). H NMR (400 MHz, CDCl ) δ 7.45 – 7.22
f
3
(m, 26.1H), 7.20 – 7.12 (m, 3.1H), 5.11 (d, J = 3.5 Hz, 1.0H), 5.04 – 4.92 (m, 2.1H), 4.89 – 4.43
(m, 11.8H), 4.29 (d, J = 1.5 Hz, 2.9H), 4.18 – 4.11 (m, 0.4H), 4.02 (t, J = 9.3 Hz, 1.1H), 3.83 –
1
3
1
3
.60 (m, 7.2H), 3.51 (t, J = 8.1 Hz, 1.0H), 2.51 – 2.43 (m, 1.7H); C{ H} NMR (100 MHz,
CDCl ) δ 138.8, 138.6, 138.4, 138.3, 138.1, 138.0, 137.9, 128.5, 128.4, 128.3, 128.2, 128.0,
3
1
7
27.9, 127.8, 127.7, 127.6, 101.5, 95.3, 84.6, 82.0, 81.9, 79.4, 79.1, 79.0, 77.7, 77.5, 75.8, 75.7,
5.1, 75.0, 74.9, 74.8, 73.5, 73.0, 70.8, 68.8, 68.4, 56.0, 54.4.
General procedure for glycosylation reaction (B). To a suspension of glycosyl donor (0.15
mmol), glycosyl acceptor (0.18 mmol, 1.2 equiv) and 4 Å MS (200 mg) in dry CH Cl (3 mL)
2
2
was added 10 mol % of AuCl at room temperature. The reaction mixture was stirred at 45 °C
3
until the completion of the reaction, monitored by TLC. After completion of the reaction, the
mixture was diluted with CH Cl and washed thrice with a cold saturated aqueous solution of
2
2
NaHCO . The combined organic phase was washed with brine solution, dried over anhydrous
3
Na SO , evaporated in vacuo and purified by column chromatography (using different fractions
2
4
of ethyl acetate in hexane as eluting solvent) to afford the desired glycosides.
14a
Isopropyl 2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranoside (14a). The product 14a was isolated
from the reaction between 2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranosyl phenylpropiolate 13a
(100 mg, 0.15 mmol, 1.0 equiv) and isopropanol (14 µL, 0.18 mmol, 1.2 equiv) following the
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general procedure B as colourless semisolid (80 mg, 92%, α/β 1:1.3). R : 0.39 (ethyl
f
1
acetate/hexane 1:10 (v/v). H NMR (400 MHz, CDCl ) δ 7.39 – 7.24 (m, 31.3H), 7.20 – 7.12 (m,
3
3.4H), 5.03 – 4.86 (m, 3.4H), 4.85 – 4.52 (m, 9.7H), 4.51 – 4.44 (m, 2.4H), 4.08 – 3.97 (m,
0
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.7H), 3.93 – 3.83 (m, 1.4H), 3.74 (d, J = 12.2 Hz, 1.7H), 3.70 – 3.60 (m, 3.5H), 3.59 – 3.52 (m,
.8H), 3.50 – 3.42 (m, 2.0H), 1.32 (d, J = 6.1 Hz, 3.0H), 1.24 (dd, J = 8.7, 6.3 Hz, 5.5H), 1.18 (d,
1
1
3
1
J = 6.0 Hz, 2.2H); C{ H} NMR (100 MHz, CDCl ) δ 139.0, 138.7, 138.6, 138.3, 138.2, 138.0,
3
1
7
28.4, 128.2, 128.0, 127.9, 127.8, 127.7, 127.6, 102.2, 94.8, 84.9, 82.4, 82.2, 80.0, 78.0, 77.9,
5.7, 75.2, 75.0, 74.8, 73.5, 73.2, 72.4, 70.1, 69.2, 69.1, 68.6, 23.8, 23.2, 22.3, 21.2.
Reisolation of phenylpropiolic acid and their utilization for the synthesis of glycosyl donor:
To a suspension of 13a (200 mg, 0.3 mmol), isopropanol (30 µL, 0.36 mmol) and 4 Å MS (400
mg) in dry CH Cl (6 mL) was added 10 mol % of AuCl at room temperature. The reaction
2
2
3
mixture was stirred at 45 °C for 1h. After 1h, the reaction mixture was diluted with CH Cl and
2
2
washed with cold saturated aqueous solution of NaHCO . The aqueous phase was acidified with
3
1(M) cold solution of hydrochloric acid and extracted three times with CH Cl . The combined
2
2
organic phase was dried over anhydrous Na SO , filtered and evaporated in vacuo to get
2
4
phenylpropiolic acid as white solid (40 mg, 91%).
The recovered phenylpropiolic acid was further coupled with 2,3,4,6-tetra-O-benzyl-α/β-D-
glucopyranose 10a to obtain 13a with 80% isolated yield.
1
4a
2
-Bromoethyl 2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranoside (14b).
The product 14b was
isolated from the reaction between 2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranosyl
phenylpropiolate 13a (100 mg, 0.15 mmol, 1 equiv) and 2-bromoethanol (13 µL, 0.18 mmol, 1.2
equiv) following the general procedure B as colourless liquid (88 mg, 91%, α/β 1.6:1). R : 0.39
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(
ethyl acetate/hexane 1:10 (v/v). H NMR (400 MHz, CDCl ) δ 7.34 – 7.12 (m, 24.5H), 7.09 –
3
7
.00 (m, 2.9H), 4.97 – 4.81 (m, 1.8H), 4.78 – 4.67 (m, 4.6H), 4.64 (d, J = 11.0 Hz, 0.4H), 4.60 –
4.45 (m, 2.8H), 4.43 – 4.34 (m, 2.5H), 4.20 – 4.08 (m, 0.4H), 3.91 (t, J = 9.3 Hz, 1.0H), 3.85 –
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3
1
9
6
.68 (m, 3.3H), 3.67 – 3.35 (m, 9.1H); C{ H} NMR (100 MHz, CDCl ) δ 138.9, 138.6, 138.5,
3
38.3, 138.2, 138.1, 137.9, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.7, 127.6, 103.8,
7.5, 84.6, 82.1, 82.0, 80.0, 77.7, 77.4, 75.8, 75.7, 75.1, 74.9, 73.5, 73.4, 70.7, 69.7, 68.9, 68.5,
8.3, 30.3, 30.0.
1
4a
3
-Chloropropyl 2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranoside (14c).
from the reaction between 2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranosyl
phenylpropiolate 13a (100 mg, 0.15 mmol, 1 equiv) and 3-chloropropanol (14 µL, 0.18 mmol,
The product 14c was
isolated
1
:
.2 equiv) following the general procedure B as colourless semi solid (80 mg, 86%, α/β 1.5:1). Rf
1
0.39 (ethyl acetate/hexane 1:10 (v/v). H NMR (400 MHz, CDCl ) δ 7.30 – 7.13 (m, 31.8H),
3
7
.06 (t, J = 7.2 Hz, 3.7H), 4.92 – 4.78 (m, 2.5H), 4.74 (dd, J = 10.4, 4.3 Hz, 3.1H), 4.69 (d, J =
3.4 Hz, 1.0H), 4.67– 4.62 (m, 1.9H), 4.60 – 4.50 (m, 2.7H), 4.49 – 4.35 (m, 3.7H), 4.31 (d, J =
.7 Hz, 0.7H), 4.22 (t, J = 5.9 Hz, 0.2H), 3.99 – 3.92 (m, 0.7H), 3.91 – 3.84 (m, 1.2H), 3.75 (dd,
7
1
3
1
J = 9.5, 5.8 Hz, 0.9H), 3.70 – 3.34 (m, 15.6H), 2.08 – 1.88 (m, 4.0H); C{ H} NMR (100 MHz,
CDCl ) δ 138.9, 138.7, 138.4, 138.3, 138.2, 138.0, 128.5, 128.4, 128.1, 128.0, 127.8, 127.7,
3
1
6
27.6, 103.7, 97.3, 84.8, 82.3, 82.1, 80.2, 77.9, 77.8, 75.7, 75.2, 75.0, 74.9, 73.6, 73.3, 70.4, 68.9,
8.6, 66.4, 64.5, 41.8, 32.9, 32.4.
1
4a
1
-Adamentanemethanol 2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranoside (14d). The product 14d
was isolated from the reaction between 2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranosyl
phenylpropiolate 13a (100 mg, 0.15 mmol, 1 equiv) and 1-adamentanemethanol (30 mg, 0.18
mmol, 1.2 equiv) following the general procedure B as semi solid (100 mg, 97%, α/β 1:1). Rf :
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