Directed Nickel-Catalyzed pseudo-Anomeric C?H Alkynylation of Glycals as an Approach towards C-Glycoconjugate Synthesis

Article abstract of DOI:10.1002/adsc.202100823

The synthesis of complex C-glycoconjugates is presented here using a key directed nickel-catalyzed C?H alkynylation step. Thanks to a bidentate amidoquinoline-type directing group, the insertion of diverse alkynyl moieties onto the pseudo-anomeric position of glycal substrates was performed on ten examples in moderate to good yields. These platforms were used as starting substrates in a click reaction with complex azides to form original C-glycoconjugates. By this route, a C-glycosylated amino acid, a C-linked disaccharide and a C-glycosylated biotin derivative were synthesized. Preliminary conditions to remove the directing group are also proposed. (Figure presented.).

Full text of DOI:10.1002/adsc.202100823

RESEARCH ARTICLE
doi.org/10.1002/adsc.202100823
Directed Nickel-Catalyzed pseudo-Anomeric CÀ H Alkynylation of
Glycals as an Approach towards C-Glycoconjugate Synthesis
Morgane de Robichon,a, b David Branquet,a, b Jacques Uziel,a, b
Nadège Lubin-Germain,a, b and Angélique Ferrya, b,*
a
CY Cergy Paris University, BioCIS, CNRS, 5 mail Gay-Lussac, 95000 Cergy-Pontoise cedex, France
E-mail: angelique.ferry@cyu.fr
Paris-Saclay University, BioCIS, CNRS, 5 rue J.-B. Clément, 92296 Châtenay-Malabry cedex, France
b
Manuscript received: July 1, 2021; Revised manuscript received: September 2, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100823
Abstract: The synthesis of complex C-glycoconjugates is presented here using a key directed nickel-catalyzed
CÀ H alkynylation step. Thanks to a bidentate amidoquinoline-type directing group, the insertion of diverse
alkynyl moieties onto the pseudo-anomeric position of glycal substrates was performed on ten examples in
moderate to good yields. These platforms were used as starting substrates in a click reaction with complex
azides to form original C-glycoconjugates. By this route, a C-glycosylated amino acid, a C-linked disaccharide
and a C-glycosylated biotin derivative were synthesized. Preliminary conditions to remove the directing group
are also proposed.
Keywords: CÀ H functionalization; Glycals; Alkynylation; Nickel catalysis; Directing group
Introduction
of C-glycoconjugates, where the glycoside moiety and
the aglycon are linked by a CÀ C bond, has been a
Natural hybrids between sugars and complex mole- point of focus. However, they are still underrepre-
cules, namely glycoconjugates, are diverse in biology sented in the literature due to the difficulty to create
and play crucial roles in many important cellular such bonds. Indeed, the description of synthesis of C-
pathways. Glycolipids and glycoproteins are the most glycoconjugates by click chemistry is scarce. These
famous members of this family, suitably exposed on structures could be obtained by using 1-alkynyl-glyco-
the cell surface to enable cell adhesion and communi- side platforms,[7] commonly synthesized by the addi-
cation processes.[1] The design of non-natural glyco- tion of a metallic alkynide onto an electrophilic sugar
conjugates which mimic natural analogues is thus an (lactone, epoxide, etc.)[8] or by Lewis acid-catalyzed
important research area for therapeutic applications.[2] reaction between a stannylated alkyne and a halogen-
Moreover, the discovery of the click reaction was a ated sugar.[9] Other methods exist employing Ferrier
major breakthrough to conjugate biomolecules by an type rearrangement on glycal substrates.[10] Recently,
easy and powerful way.[3] Especially, the Huisgen we proposed an access to C-glycosides through a
cycloaddition between an alkyne and an azide has been palladium-catalyzed CÀ H functionalization of glycal
the most commonly used in this field.[4] The synthesis substrates, directed by a suitable bidentate amide-type
of glycoconjugates using this reactivity mainly in- directing group placed at the position 2 (Scheme 1).[11]
volves 1-azidoglycoside partners giving rise, after click This strategy enabled to target the desired pseudo-
reaction, to conjugates where the sugar part is linked to anomeric position (position 1). This work represents
an aglycon via a hydrolyzable CÀ N anomeric bond.[5] the unique example of a directed CÀ H functionaliza-
Alternatively to this strategy, the sugar can be fixed to tion process on glycals. However, this proof of concept
carry the alkyne functionality, generally introduced by was limited only to aryl and activated alkenyl iodide
a glycosylation reaction in the presence of propargylic partners. The introduction of alkyne moieties was
alcohol leading to a hydrolyzable CÀ O anomeric unsuccessful in these conditions. In the literature, CÀ H
link.[6] To ensure stability, which is one of the success functionalization of sugars are very limited.[12] This
factor for potential drug candidates, the development reactivity, applied on glycals in the absence of a
Adv. Synth. Catal. 2021, 363, 1–12
1
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

RESEARCH ARTICLE
asc.wiley-vch.de
Table 1. Optimization of the CÀ H functionalization
conditions.[a]
°
N
[Ni]
(mol%)
L
Tol
T
1H NMR
°
(mol%) (mL) ( C) Yield 2a/1a
1
2
3
4
5
6
NiCl2 (10)
–
–
Ni(acac)2 (10)
Ni(acac)2 (20) 80
Ni(OAc)2.
4H2O (20)
40
–
–
0.85 120 17%/70%
–
–
–
–
–
140 25%/37%
150 15%/45%
140 21%/59%
–
–
–
30%/53%
42%/traces
–
–
Scheme 1. The proposed methodology versus previous works
on CÀ H functionalization of glycals.
7
Ni(NO3)2.
–
–
46%/27%
6H2O (20)
8
9
–
–
–
–
–
–
w/o
–
–
0.43
1.7
0.43
–
–
–
–
–
–
48%/0%
directing group, led almost exclusively to the function-
alization of the position 2 with perfluoroalkylated,
alkene-type or borylated functionalities only
(Scheme 1).
25%/45%
38%/43%
58%/25%
65%[c]/25%
10
11[b]
12[b] Ni(OAc)2.
4H2O (20)
–
Recently, Li et al. described the introduction of an
alkyne on a single example of dihydropyran scaffold
using a nickel-catalyzed process directed by an
amidoquinoline group.[13] The literature on CÀ H
alkynylation reactions has mostly developed over this
last decade but is still limited.[14] Most of the described
[a] The reaction was performed on 0.085 mmol scale of 1a.
[b]
°
[Ni] was added after 4 h of stirring at 140 C.
[c] 64% isolated.
methodologies use palladium or rhodium catalysis[15] higher degree of degradation with Ni(OAc)2.4H2O
and only a few examples cover nickel-catalyzed compared to Ni(NO3)2.6H2O (Table 1, entries 4–7).
reactivity.[16] Due to the failure of alkyne moiety The quantity of solvent can be reduced by half without
introduction by our previous palladium-catalyzed CÀ H loss of yield but the reactivity was lower if the quantity
functionalization, we present, herein, a directed nickel- of solvent is doubled (Table 1, entries 8 and 9). The
catalyzed CÀ H alkynylation of the pseudo-anomeric absence of ligand resulted in a slight decrease in the
position of C2-amidoglycals. The resulting 1-alkynyl- observed yield, but the presence of reactivity in this
glycosides are ready-to-use for the synthesis of case (38% yield in 2a) allowed us to consider further
complex C-glycoconjugates (Scheme 1).
investigations without ligand (Table 1, entry 10). Fi-
nally, the key parameter was the postponed addition of
the nickel reagent after four hours of heating (where
Results and Discussion
°
1a, 3a and the base were stirred in toluene at 140 C)
Based on the work of Li et al.,[13] we started our leading to 2a in a good yield of 58% using Ni-
investigation by heating glycal 1a (obtained in four (NO3)2.6H2O and 65% (64% isolated) using Ni-
steps from commercial 2,4,6-tri-OAc-d-glucal) up to (OAc)2.4H2O (Table 1, entries 11 and 12). The role of
°
120 C in toluene in the presence of NiCl2 as catalyst, this pre-heating step in the reactivity is quite unclear.
TMEDA as a ligand, Na2CO3 as a base and bromo The first plausible hypothesis is that the reaction
(triisopropylsilyl)acetylene (3a) as an electrophile proceeds if some amount of the base is solubilized in
(Table 1). Under these conditions, the desired com- the medium. However, the solubilization of Na2CO3 is
pound 2a was obtained. However, the yield was slow and limited in the chosen solvent, namely toluene.
1
limited to 17% by H NMR due to a low conversion Another explanation may be that the process only
(70% of the remaining starting material 1a, Table 1, works when the sugar 1a adopts a particular con-
entry 1). Testing of different temperatures revealed that formation, formed at high temperature due to the
the optimal balance between reactivity and degradation presence of other electron π-enriched reagents such as
°
is obtained at 140 C (Table 1, entries 1–3). In terms of 3a or by the presence of the base. It should be noticed
catalysts, 20 mol% of Ni(OAc)2.4H2O or Ni- that chloro(triisopropylsilyl)acetylene is completely
(NO3)2.6H2O provided the best yields of 2a with a unreactive under the optimized conditions and only
Adv. Synth. Catal. 2021, 363, 1–12
2
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

RESEARCH ARTICLE
asc.wiley-vch.de
20% of 2a (1H NMR) was observed using iodo tion of the desired product 2 and releases the Ni(II)
(triisopropylsilyl)acetylene as electrophilic partner.
catalyst via IV.
According to Liu’s hypothesis,[13] the mechanism is
Under these optimal conditions, versatility in terms
supposed to start with the complexation of the Ni(II) of electrophilic partners and glycal structures was
species to the amidoquinoline-type directing group explored (Table 2).
forming the intermediate I (Scheme 2). With the help
Generally, silylated alkynyl bromides are well
of the base, the nickel species would insert into the tolerated and allow access to the corresponding 1-
close CÀ H bond, providing intermediate II. Then, the alkynylglycosides in moderate to good yields (Table 2,
oxidative addition step leads to the Ni(IV) complex 2a-e). Alkynyl partners bearing alkyl or aryl moieties
1
III. Finally, reductive elimination leads to the forma- led to low yields (<10% in H NMR) except for
bromocyclopropylacetylene, which formed the corre-
sponding product 2f in moderate yield. While d-
galactal showed similar reactivity to that observed with
the d-glucal analogues (Table 2, 4a and 4b), the l-
rhamnal examples led to lower yields (Table 2, 5a and
5b). From these C-alkynylglycosides, the synthesis of
C-glycoconjugates by click chemistry was then ex-
plored. The removal of the silylated part of 2a using a
fluorinated reagent was tested without success. Indeed,
1
a complex mixture was observed by H-NMR in the
crude. We expected that the proximity of the nitrogen-
containing amide function could give rise to undesired
intramolecular reactivities. A preliminary protection of
the amide-type directing group by a tert-butoxycarbon-
yl group was thus performed, forming the product 6 in
a very good yield (Table 3).
Sequential one-pot cleavage of the silylated moiety
followed by the copper-catalyzed click reaction with
Table 3. Functionalization of 2a by click reaction.
Scheme 2. Proposed mechanistic pathway.
Table 2. Scope of the CÀ H alkynylation.
Adv. Synth. Catal. 2021, 363, 1–12
3
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

RESEARCH ARTICLE
asc.wiley-vch.de
benzyl azide successfully generated the corresponding
C-glycoconjugate in a very good yield of 72%
(Table 3, 7a). This sequence was repeated with diverse
complex azide partners. A C-glycosylated amino acid
analogue (Table 3, 7b), a C-linked disaccharide
(Table 3, 7c) and a C-glycosylated biotin derivative
(Table 3, 7d) were synthesized in moderate to good
yields (39–73%). We then investigated the possibility
of removing the amidoquinoline-type directing group
on 7a. Conventional conditions described for trans-
forming amidoquinoline moieties into amide, carbox-
ylic acid, ester, etc. using basic, acidic or reductive
conditions[17] did not yield the desired product. We
finally partially solved the problem by using pyrroli-
Experimental Section
Materials and Methods
All chemical operations were carried out using standard screw
sealed tubes. Acetonitrile was purified before use by distillation
under an argon atmosphere. Other solvents were used without
further purification. The “Cyclo” abbreviation will be used to
name cyclohexane. Commercially available chemicals were
used as received unless otherwise stated. Reactions were
monitored by thin-layer chromatography on silica gel plates (60
F254 aluminum sheets) which were rendered visible by ultra-
violet and/or spraying with vanillin (15%)+sulfuric acid
1
(2,5%) in EtOH followed by heating. H NMR (400 MHz), and
13C NMR (100.5 MHz) were recorded on a BRUKER AVANCE
NEO 400 MHz spectrometer at 298 K unless otherwise stated.
Chemical shifts are given in ppm (δ) and are referenced to the
internal solvent signal or to TMS used as an internal standard.
Multiplicities are declared as follows: s (singlet), bs (broad
singlet), d (doublet), t (triplet), q (quadruplet), dd (doublet of
doublet), ddd (doublet of doublet of doublet), dt (doublet of
triplet), m (multiplet). Coupling constants J are given in Hz.
Infrared spectra (IR) were recorded on BRUKER TENSOR 27
on a FT-IR system using diamond window Dura SamplIR II,
and the data are reported in reciprocal centimeters (cmÀ 1) in the
range 4000À 600 cmÀ 1. Optical rotations were measured on an
Anton Paar MCP 200 polarimeter at 589 nm. [α] is expressed in
deg.cm3.gÀ 1.dmÀ 1, and c is expressed in g/100 cm3. HRMS were
determined on a QTOF mass analyzer coupled with electrospray
ionization (ESI) or atmospheric pressure chemical ionization
(APCI) with a resolution of 12000.
°
dine in toluene at 65 C, which formed the desired
amido-glycal 8 in 35% yield but accompanied by 41%
of an undesired compound 9 coming from the
competitive deprotection of the tert-butoxycarbonyl
group (Scheme 3).
Conclusion
A novel approach towards 1-alkynylglycosides has
been presented using a directed nickel-catalyzed CÀ H
alkynylation process between C2-amidoglycal starting
substrates and alkynyl bromides as electrophilic
reagents. Various examples bearing diversely substi-
tuted alkyne moieties and possessing different glycal
configurations were successfully synthesized in moder-
ate to good yields using this procedure. The addition of
the nickel catalyst after 4 hours of heating was crucial
to obtain good reactivity. A mechanistic investigation
to explain this particularity is planned in the near
future. After a preliminary protection step of the
amide-type directing group and the removal of the
silylated moiety, these alkynylated compounds were
engaged in a copper-catalyzed click reaction with
azides. Complex amino acid, glycosidic and biotin-
type azides were chosen to give rise to original C-
glycoconjugates. A procedure to remove the amidoqui-
noline group was finally presented.
Synthetic Procedures
Compounds 2-iodo-3,4,6-tri-O-benzyl-d-glucal and 2-iodo-
3,4,6-tri-O-benzyl-d-galactal were prepared according to the
literature:[18] corresponding glycal was dissolved in dry
acetonitrile (8 mL/mmol) under argon, and the resulting mixture
°
was heated to 80 C. At this temperature, N-iodosuccinimide
(1.2 equiv.) and silver nitrate (20 mol%) were added. The
°
resulting mixture was stirred at 80 C for 1–2 h. The mixture
was filtrated on Celite with EtOAc and concentrated with silica.
The obtained crude was purified on silica gel and furnished the
corresponding 2-iodo-tri-O-benzylglycal. Compounds 2-N-(qui-
nolin-8-yl)carbamoyl-3,4,6-tri-O-benzyl-d-glucal and 2-N-(qui-
nolin-8-yl)carbamoyl-3,4,6-tri-O-benzyl-d-galactal were pre-
pared according to the literature:[11] in a sealed tube were added
Pd(OAc)2 (0.1 equiv.), PPh3 (0.2 equiv.), K2CO3 (2 equiv.),
Mo(CO)6 (4.2 equiv.), 8-aminoquinoline (2 equiv.) and the
corresponding 2-iodoglucal (1 equiv.). Dioxane (9.8 mL/mmol)
°
was then added and the resulting mixture was stirred at 80 C
overnight. The mixture was filtered on celite, concentrated
under vacuum and the crude was finally purified on silica gel
using the indicated solvent. The product was washed with HCl
(1 M) to remove excess of aminoquinoline and then with a
saturated
aqueous
solution
of
NaHCO3.
Bromo
(triisopropylsilyl)acetylene, (bromoethynyl)triphenylsilane, 1-
bromo-2-(tert-butyldimethylsilyl)acetylene, bromo(triethylsilyl)
acetylene,
(bromoethynyl)cyclopropane,
(bromoethynyl)
dimethyl(phenyl)silane were prepared according to the
literature:[19] corresponding alkyne was dissolved in acetone
Scheme 3. Removal of the directing group.
Adv. Synth. Catal. 2021, 363, 1–12
4
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

RESEARCH ARTICLE
asc.wiley-vch.de
(5.4 mL/mmol), NBS (1.2 equiv.) and AgNO3 (0.1 equiv.) were
added and the resulting mixture was stirred 2 h at room
temperature. The reaction was quenched with water, the crude
was extracted with pentane (×3) and the combined organic
fractions were dried over anhydrous Na2SO4 and concentrated
under vacuum.
Characterization Data
2-N-(quinolin-8-yl)carbamoyl-1-((triisopropylsilyl)ethynyl)-
3,4,6-tri-O-benzyl-d–glucal (2a). 2a was obtained following
the general procedure of CÀ H functionalization: in a sealed tube
were added Na2CO3 (31.6 mg, 5 equiv., 0.298 mmol), bromo
(triisopropylsilyl)acetylene (17.4 μL, 1.2 equiv., 0.072 mmol),
compound 1a (35 mg, 1 equiv., 0.060 mmol) and toluene
°
(0.3 mL). The resulting mixture was stirred for 4 h at 140 C.
Then Ni(OAc)2.4H2O (3 mg, 20 mol%, 0.012 mmol) was added
at room temperature in the sealed tube. The resulting mixture
General Procedures
General Procedure for the CÀ H Functionalization
Reaction (Compounds 2, 4, 5)
°
was stirred at 140 C overnight. The mixture was filtrated on
celite with EtOAc and then concentrated under vacuum. 2a was
obtained after purification on silica gel (eluent: Cyclo/EtOAc
85:15) as yellowish oil (29.4 mg; 0.038 mmol; 64%). H NMR
In a sealed tube were added Na2CO3 (5 equiv.), alkyne bromide
(1.2 equiv.), compound 1a (1 equiv.) and toluene (5.1 mL/
mmol). The resulting mixture was stirred for 4 h at 140 C.
Then Ni(OAc)2.4H2O (20 mol%) was added at room temper-
1
°
(400 MHz, CDCl3) δ 10.35 (s, 1H), 8.75 (dd, J=7.4, 1.3 Hz,
1H), 8.64 (dd, J=4.2, 1.6 Hz, 1H), 8.07 (dd, J=8.3, 1.5 Hz,
1H), 7.47 (t, J=7.8 Hz, 1H), 7.42 (dd, J=8.2, 1.3 Hz, 1H),
7.34 (dd, J=8.3, 4.2 Hz, 1H), 7.28–7.18 (m, 11H), 7.10 (dd,
J=6.8, 2.7 Hz, 2H), 7.05 (dd, J=5.2, 1.7 Hz, 2H), 4.70 (dd,
J=4.0, 1.1 Hz, 1H), 4.66 (d, J=11.2 Hz, 1H), 4.64 (d, J=
11.8 Hz, 1H), 4.55 (d, J=11.8 Hz, 1H), 4.52–4.49 (m, 3H),
4.42–4.37 (m, 1H), 3.92 (dd, J=4.8, 4.4 Hz, 1H), 3.81 (dd, J=
10.9, 5.9 Hz, 1H), 3.71 (dd, J=10.9, 4.5 Hz, 1H), 0.75–0.69
(m, 21H); 13C NMR (101 MHz, CDCl3) δ 165.4, 148.2, 138.9,
138.8, 138.3, 138.2, 137.9, 136.3, 135.0, 128.6, 128.5, 128.3,
128.1, 128.0, 128.0, 127.8, 127.8, 127.6, 127.5, 121.6, 121.5,
117.2, 117.1, 99.4, 98.4, 77.6, 73.4, 73.3, 73.3, 72.6, 72.5, 67.7,
18.4, 18.3, 11.1; IR (cmÀ 1): 2925, 2859, 2363, 1684, 1559,
1526, 1487, 1457, 1374, 1326, 1261, 1208, 1145, 1091;
[α]20D = +36.1 (0.33, CHCl3); HRMS (TOF ES+) for (M+
H)+ C48H55N2O5Si+ (m/z): calc. 767.3880; found 767.3889.
ature in the sealed tube. The resulting mixture was stirred at
°
140 C overnight. The mixture was filtrated on celite with
EtOAc and then concentrated under vacuum. The crude was
finally purified on silica gel using the indicated solvent.
General Procedure for the 1H NMR Yield Determi-
nation
The NMR yield of 2a was determined with acetophenone as
internal reference: 1 equiv. of acetophenone compared to
compound 1a was added after filtration of the crude on celite,
and then the crude was concentrated. The NMR yield of 2a on
1
the H NMR spectra could be determined by analytical signals:
*
s at 2.6 ppm (CH3 of acetophenone – calibrated for 3H)
compared with the integrations of product signals: s at
10.35 ppm (NH of product 2a), dd at 8.75 ppm, dd at
8.65 ppm and dd at 8.07 ppm (aromatic H of aminoquinoline
of 2a)
2-N-(quinolin-8-yl)carbamoyl-1-((triphenylsilyl)ethynyl)-
3,4,6-tri-O-benzyl-d–glucal (2b). 2b was obtained following
the general procedure of CÀ H functionalization: in a sealed tube
were added Na2CO3 (45.1 mg, 5 equiv., 0.426 mmol), (bromoe-
thynyl)triphenylsilane (37.1 mg, 1.2 equiv., 0.102 mmol), com-
pound 1a (50 mg, 1 equiv., 0.085 mmol) and toluene (0.43 mL).
The resulting mixture was stirred for 4 h at 140 C. Then
Ni(OAc)2.4H2O (4.2 mg, 20 mol%, 0.017 mmol) was added at
room temperature in the sealed tube. The resulting mixture was
stirred at 140 C overnight. The mixture was filtrated on celite
with EtOAc and then concentrated under vacuum. 2b was
obtained after purification on silica gel (eluent: Toluene/EtOAc
98:2) as yellowish oil (29.9 mg; 0.034 mmol; 40%). H NMR
The reaction yield was determined with the mean value of these
integrations. Conversion of starting material 1a was determined
in the same mixture by integration of:
°
*
s at 10.55 ppm (amide proton of 1a)
dd at 8.83 ppm, at 8.37 ppm and at 8.12 ppm (aromatic H of
*
aminoquinoline of 1a)
°
The mean value of these integrations was calculated determin-
ing the conversion of reaction.
1
(400 MHz, CDCl3) δ 10.68 (s, 1H), 8.82–8.80 (m, 1H), 7.93
(dd, J=4.2, 1.5 Hz, 1H), 7.89 (dd, J=8.3, 1.5 Hz, 1H), 7.58
(dd, J=7.9, 1.4 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.39 (d, J=
7.4 Hz, 1H), 7.34–7.32 (m, 7H), 7.29–7.27 (m, 4H), 7.23–7.18
(m, 5H), 7.14–7.09 (m, 6H), 7.06–7.00 (m, 8H), 4.80 (dd, J=
3.6, 1.2 Hz, 1H), 4.69 (d, J=11.2 Hz, 1H), 4.65 (d, J=12.0 Hz,
1H), 4.57–4.47 (m, 5H), 3.95 (t, J=4.1 Hz, 1H), 3.84 (dd, J=
10.7, 6.2 Hz, 1H), 3.71 (dd, J=10.7, 4.7 Hz, 1H); 13C NMR
(101 MHz, CDCl3) δ 164.8, 148.2, 138.7, 138.7, 138.3, 138.1,
137.7, 135.8, 135.6, 135.1, 134.9, 132.1, 130.2, 130.0, 128.6,
128.5, 128.3, 128.1, 128.0, 128.0, 127.9, 127.8, 127.8, 127.6,
127.3, 121.7, 121.4, 117.9, 116.8, 100.2, 98.1, 77.6, 73.4, 73.2,
72.4, 72.3, 72.2, 67.7; IR (cmÀ 1): 3067, 3029, 2913, 2865, 2359,
1660, 1598, 1577, 1559, 1524, 1486, 1454, 1429, 1387, 1327,
1262, 1207, 1115, 1071, 1028; [α]20D = +175.4 (1.00, CHCl3);
General Procedure for the Click Reaction (Com-
pounds 7)
In a flask, starting material was dissolved in dry THF (11 mL/
mmol) under argon. Then triethylamine (3 equiv.) and TBAF
(1.5 equiv.) were added and the reaction was stirred at room
temperature. The color of the reaction mixture changed in
purple and after that, CuI (0.5 equiv.) and azide partner
°
(1.5 equiv.) were added. The reaction was stirred at 40 C
overnight. The mixture was concentrated under vacuum and the
crude was finally purified on silica gel using the indicated
solvent.
Adv. Synth. Catal. 2021, 363, 1–12
5
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

RESEARCH ARTICLE
asc.wiley-vch.de
HRMS (TOF ES+) for (M+H)+ C57H49N2O5Si+ (m/z): calc.
869.3411; found 869.3406.
2933, 2874, 2360, 1734, 1662, 1598, 1577, 1559, 1525, 1487,
1455, 1425, 1386, 1327, 1264, 1206, 1124, 1088, 1072, 1028;
[α]20D = +201.5 (1.00, CHCl3); HRMS (TOF ES+) for (M+
H)+ C45H49N2O5Si+ (m/z): calc. 725.3411; found 725.3415.
2-N-(quinolin-8-yl)carbamoyl-1-((tert-butyldimethylsilyl)
ethynyl)-3,4,6-tri-O-benzyl-d–glucal (2c). 2c was obtained
following the general procedure of CÀ H functionalization: in a
sealed tube were added Na2CO3 (41.5 mg, 5 equiv.,
2-N-(quinolin-8-yl)carbamoyl-1-((dimethyl(phenyl)silyl)
ethynyl)-3,4,6-tri-O-benzyl-d–glucal (2e). 2e was obtained
following the general procedure of CÀ H functionalization: in a
sealed tube were added Na2CO3 (45.2 mg, 5 equiv.,
0.426 mmol), (bromoethynyl)dimethyl(phenyl)silane (19.3 μL,
1.2 equiv., 0.102 mmol), compound 1a (50 mg, 1 equiv.,
0.085 mmol) and toluene (0.43 mL). The resulting mixture was
0.426 mmol),
1-Bromo-2-(tert-butyldimethylsilyl)acetylene
(19.7 μL, 1.2 equiv., 0.102 mmol), compound 1a (50 mg,
1 equiv., 0.085 mmol) and toluene (0.43 mL). The resulting
°
mixture was stirred for 4 h at 140 C. Then Ni(OAc)2.4H2O
(4.2 mg, 20 mol%, 0.017 mmol) was added at room temperature
°
°
in the sealed tube. The resulting mixture was stirred at 140 C
stirred for 4 h at 140 C. Then Ni(OAc)2.4H2O (4.2 mg,
20 mol%, 0.017 mmol) was added at room temperature in the
overnight. The mixture was filtrated on celite with EtOAc and
then concentrated under vacuum. 2c was obtained after
purification on silica gel (eluent: Toluene/EtOAc 95:5) as
yellowish oil (37.9 mg; 0.052 mmol; 61%). 1H NMR
(400 MHz, CDCl3) δ 10.52 (s, 1H), 8.86 (dd, J=7.5, 1.2 Hz,
1H), 8.76 (dd, J=4.2, 1.6 Hz, 1H), 8.16 (dd, J=8.3, 1.5 Hz,
1H), 7.57 (t, J=7.9 Hz, 1H), 7.51 (dd, J=8.2, 1.2 Hz, 1H),
7.43 (dd, J=8.3, 4.2 Hz, 1H), 7.37–7.30 (m, 10H), 7.22–7.15
(m, 5H), 4.81 (dd, J=3.7, 1.2 Hz, 1H), 4.75 (d, J=11.4 Hz,
1H), 4.72 (d, J=12.4 Hz, 1H), 4.64–4.57 (m, 4H), 4.54–4.50
(m, 1H), 4.00 (t, J=4.2 Hz, 1H), 3.89 (dd, J=10.7, 6.0 Hz,
1H), 3.78 (dd, J=10.7, 4.8 Hz, 1H), 0.66 (s, 9H), À 0.16 (s,
3H), À 0.26 (s, 3H).13C NMR (101 MHz, CDCl3) δ 165.2,
148.3, 138.9, 138.9, 138.2, 138.1, 137.8, 136.3, 134.9, 128.6,
128.5, 128.3, 128.1, 128.0, 127.9, 127.8, 127.8, 127.6, 127.5,
121.6, 117.2, 116.9, 101.2, 97.3, 77.4, 73.4, 73.2, 72.7, 72.4,
72.3, 67.6, 25.8, 16.5, À 5.3, À 5.4; IR (cmÀ 1) : 3030, 2953,
2928, 2858, 2360, 1662, 1598, 1577, 1524, 1486, 1471, 1455,
°
sealed tube. The resulting mixture was stirred at 140 C
overnight. The mixture was filtrated on celite with EtOAc and
then concentrated under vacuum. 2e was obtained after
purification on silica gel (eluent: Toluene/EtOAc 98:2) as
yellowish oil (14.4 mg; 0.019 mmol; 22%). 1H NMR
(400 MHz, CDCl3) δ 10.65 (s, 1H), 8.86 (dd, J=7.6, 1.2 Hz,
1H), 8.51 (dd, J=4.2, 1.6 Hz, 1H), 8.10 (dd, J=8.3, 1.6 Hz,
1H), 7.56 (t, J=7.9 Hz, 1H), 7.49 (dd, J=8.3, 1.1 Hz, 1H),
7.35–7.29 (m, 13H), 7.20–7.16 (m, 6H), 7.07 (t, J=7.4 Hz,
2H), 4.83 (dd, J=3.6, 1.4 Hz, 1H), 4.74 (d, J=11.2 Hz, 1H),
4.70 (d, J=11.9 Hz, 1H), 4.60 (d, J=11.8 Hz, 1H), 4.58 (d, J=
11.3 Hz, 1H), 4.57–4.52 (m, 3H), 3.98 (t, J=3.9 Hz, 1H), 3.88
(dd, J=10.7, 6.3 Hz, 1H), 3.75 (dd, J=10.7, 4.8 Hz, 1H), 0.11
(s, 3H), 0.06 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 165.0,
148.3, 139.0, 138.8, 138.3, 138.1, 137.8, 136.2, 135.3, 134.9,
133.6, 129.5, 128.6, 128.6, 128.3, 128.1, 128.0, 128.0, 127.8,
127.8, 127.7, 127.7, 127.5, 121.6, 121.6, 117.4, 116.8, 101.1,
98.0, 77.4, 73.4, 73.2, 72.3, 72.1, 72.1, 67.7, À 1.6, À 1.7; IR
(cmÀ 1): 3063, 3030, 2960, 2919, 2865, 2359, 2339, 1734, 1718,
1700, 1654, 1598, 1577, 1559, 1525, 1497, 1487, 1455, 1427,
1425, 1386, 1327, 1250, 1206, 1090, 1071, 1028; [α]20
=
D
+207.6 (1.00, CHCl3); HRMS (TOF ES+) for (M+H)+
C45H49N2O5Si+ (m/z): calc. 725.3411; found 725.3418.
1387, 1327, 1251, 1206, 1178, 1118,1091, 1071, 1028; [α]20
=
D
2-N-(quinolin-8-yl)carbamoyl-1-((triethylsilyl)ethynyl)-3,4,6-
tri-O-benzyl-d–glucal (2d). 2d was obtained following the
general procedure of CÀ H functionalization: in a sealed tube
were added Na2CO3 (48.9 mg, 5 equiv., 0.426 mmol), bromo
(triethylylsilyl)acetylene (19.7 μL, 1.2 equiv., 0.102 mmol),
compound 1a (50 mg, 1 equiv., 0.085 mmol) and toluene
+171.7 (1.00, CHCl3); HRMS (TOF ES+) for (M+H)+
C47H45N2O5Si+ (m/z): calc. 745.3098; found 745.3105.
2-N-(quinolin-8-yl)carbamoyl-1-(cyclopropylethynyl)-3,4,6-
tri-O-benzyl-d–glucal (2f). 2f was obtained following the
general procedure of CÀ H functionalization: in a sealed tube
were added Na2CO3 (45.2 mg, 5 equiv., 0.426 mmol), (bromoe-
thynyl)cyclopropane (9.6 μL, 1.2 equiv., 0.102 mmol), com-
pound 1a (50 mg, 1 equiv., 0.085 mmol) and toluene (0.43 mL).
°
(0.43 mL). The resulting mixture was stirred for 4 h at 140 C.
Then Ni(OAc)2.4H2O (4.2 mg, 20 mol%, 0.017 mmol) was
added at room temperature in the sealed tube. The resulting
°
°
mixture was stirred at 140 C overnight. The mixture was
The resulting mixture was stirred for 4 h at 140 C. Then
Ni(OAc)2.4H2O (4.2 mg, 20 mol%, 0.017 mmol) was added at
room temperature in the sealed tube. The resulting mixture was
filtrated on celite with EtOAc and then concentrated under
vacuum. 2d was obtained after purification on silica gel (eluent:
Toluene/EtOAc 98:2) as yellowish oil (25.6 mg; 0.035 mmol;
°
stirred at 140 C overnight. The mixture was filtrated on celite
with EtOAc and then concentrated under vacuum. 2f was
1
41%). H NMR (400 MHz, CDCl3) δ 10.55 (s, 1H), 8.86 (dd,
J=7.5, 1.1 Hz, 1H), 8.77 (dd, J=4.1, 1.5 Hz, 1H), 8.16 (dd,
J=8.3, 1.4 Hz, 1H), 7.58–7.54 (m, 1H), 7.51 (dd, J=8.2,
1.2 Hz, 1H), 7.44 (dd, J=8.3, 4.2 Hz, 1H), 7.40–7.37 (m, 2H),
7.35–7.31 (m, 8H), 7.21–7.16 (m, 5H), 4.81 (dd, J=3.6,
1.1 Hz, 1H), 4.74 (d, J=11.2 Hz, 1H), 4.71 (d, J=11.8 Hz,
1H), 4.63–4.57 (m, 4H), 4.54–4.51 (m, 1H), 3.99 (t, J=4.1 Hz,
1H), 3.89 (dd, J=10.7, 6.1 Hz, 1H), 3.77 (dd, J=10.7, 4.7 Hz,
1H), 0.68 (t, J=7.9 Hz, 9H), 0.35–0.19 (m, 6H); 13C NMR
(101 MHz, CDCl3) 192.6, 165.3, 148.2, 139.0, 138.9, 138.3,
138.1, 137.8, 136.3, 135.0, 134.6, 129.9, 129.1, 129.1, 128.7,
128.6, 128.5, 128.3, 128.1, 128.0, 127.9, 127.8, 127.8, 127.6,
127.6, 121.6, 121.6, 117.1, 116.9, 100.8, 97.7, 77.4, 73.4, 73.2,
72.5, 72.4, 72.2, 67.6, 7.1, 3.7; IR (cmÀ 1): 3063, 3030, 2957,
obtained after purification on silica gel (eluent: Toluene/EtOAc
1
98:2) as yellowish oil (15.9 mg; 0.024 mmol; 29%). H NMR
(400 MHz, CDCl3) δ 10.46 (s, 1H), 8.71 (dd, J=7.1, 2.2 Hz,
2H), 8.10 (dd, J=8.3, 1.4 Hz, 1H), 7.52–7.45 (m, 2H), 7.40–
7.37 (m, 3H), 7.31–7.26 (m, 8H), 7.23–7.21 (m, 5H), 5.08 (d,
J=4.2 Hz, 1H), 4.85 (d, J=11.9 Hz, 2H), 4.57–4.54 (m, 3H),
4.21–4.17 (m, 1H), 3.92 (dd, J=8.9, 1.7 Hz, 1H), 3.78–3.71
(m, 2H), 3.43 (d, J=4.2 Hz, 1H), 0.76–0.70 (m, 1H), 0.43–0.25
(m, 4H); 13C NMR (101 MHz, CDCl3) δ 168.2, 148.5, 140.7,
138.6, 138.4, 138.2, 137.7, 136.3, 134.3, 128.5, 128.4, 128.2,
128.2, 128.0, 127.9, 127.8, 127.7, 127.5, 127.4, 126.1, 121.9,
121.8, 121.5, 116.6, 80.2, 78.8, 77.9, 77.0, 73.6, 71.4, 69.2,
62.1, 54.1, 7.8, 6.2; IR (cmÀ 1): 3318, 3064, 3030, 3008, 2925,
Adv. Synth. Catal. 2021, 363, 1–12
6
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

RESEARCH ARTICLE
asc.wiley-vch.de
2865, 2360, 2339, 1718, 1681, 1596, 1577, 1527, 1486, 1454,
1425, 1386, 1328, 1264, 1208, 1179, 1153, 1095, 1071, 1028;
[α]20D =-40.8 (1.00, CHCl3); HRMS (TOF ES+) for (M+H)+
128.0, 127.9, 127.8, 127.4, 125.9, 121.9, 121.8, 116.4, 82.1,
79.7, 74.1, 73.6, 73.1, 72.2, 68.0, 62.7, 53.4, 8.3, 7.8, 5.7; IR
(cmÀ 1): 3017, 2926, 2856, 2360, 1734, 1674, 1597, 1577, 1528,
1487, 1455, 1426, 1387, 1329, 1215, 1180, 1093, 1044, 1028;
[α]20D =-51.7 (0.88, CHCl3); HRMS (TOF ES+) for (M+H)+
+
C42H39N2O5 (m/z): calc. 651.2859; found 651.2865.
2-N-(quinolin-8-yl)carbamoyl-1-((triisopropylsilyl)ethynyl)-
3,4,6-tri-O-benzyl-d–galactal (4a). 4a was obtained following
the general procedure of CÀ H functionalization: in a sealed tube
were added Na2CO3 (36.1 mg, 5 equiv., 0.341 mmol), bromo
(triisopropylsilyl)acetylene (19.9 μL, 1.2 equiv., 0.082 mmol),
2-N-(quinolin-8-yl)carbamoyl-3,4,6-tri-O-benzyl-d-galactal
(40 mg, 1 equiv., 0.068 mmol) and toluene (0.34 mL). The
+
C42H39N2O5 (m/z): calc. 651.2859; found 651.2860.
2-N-(quinolin-8-yl)carbamoyl-1-((triisopropylsilyl)ethynyl)-
3,4-O-benzyl-l–rhamnal (5a). 3,4-di-O-benzyl-l-rhamnal was
prepared according to the literature.[20] 2-Iodo-3,4-di-O-benzyl-
l-rhamnal (S1) was synthesized following the described
procedure:[18]
3,4-di-O-benzyl-l-rhamnal
(1 g,
1 equiv.,
°
resulting mixture was stirred for 4 h at 140 C. Then Ni-
(OAc)2.4H2O (3.4 mg, 20 mol%, 0.014 mmol) was added at
room temperature in the sealed tube. The resulting mixture was
3.22 mmol) was dissolved in dry acetonitrile (22 mL) under
°
argon and the resulting mixture was heated to 80 C. At this
temperature,
N-iodosuccinimide
(870 mg,
1.2 equiv.,
°
stirred at 140 C overnight. The mixture was filtrated on celite
with EtOAc and then concentrated under vacuum. 4a was
obtained after purification on silica gel (eluent: Cyclo/EtOAc
9:1) as yellowish oil (32.5 mg; 0.042 mmol; 62%). H NMR
3.87 mmol) and silver nitrate (109 mg, 20 mol%, 0.64 mmol)
°
were added. The resulting mixture was stirred at 80 C for 2 h.
The mixture was filtrated on celite with EtOAc and concen-
trated with silica. The obtained crude was purified on silica gel
(eluent: Cyclo/EtOAc 95:5) and furnished S1 as a colorless oil
(942 mg, 2.16 mmol, 67%) which was directly engaged in the
1
(400 MHz, CDCl3) δ 10.34 (s, 1H), 8.75 (dd, J=7.3, 1.0 Hz,
1H), 8.65 (dd, J=4.1, 1.4 Hz, 1H), 8.06 (dd, J=8.3, 1.4 Hz,
1H), 7.49–7.45 (m, 1H), 7.44–7.42 (m, 1H), 7.34 (dd, J=8.3,
4.2 Hz, 1H), 7.31 (d, J=4.2 Hz, 4H), 7.27–7.21 (m, 6H), 7.19–
7.17 (m, 2H), 7.13–7.09 (m, 3H), 4.79 (d, J=3.1 Hz, 1H), 4.72
(d, J=12.0 Hz, 1H), 4.71 (d, J=11.5 Hz, 1H), 4.67 (d, J=
11.5 Hz, 1H), 4.56 (d, J=12.0 Hz, 1H), 4.56 (d, J=12.1 Hz,
1H), 4.49 (d, J=12.1 Hz, 1H), 4.46–4.45 (m, 1H), 3.99–3.91
(m, 2H), 3.83 (dd, J=11.4, 3.4 Hz, 1H), 0.74–0.68 (m, 21H);
13C NMR (101 MHz, CDCl3) δ 165.3, 148.2, 138.9, 138.6,
138.4, 138.3, 137.9, 136.2, 135.0, 128.6, 128.5, 128.2, 128.0,
128.0, 127.9, 127.7, 127.4, 121.6, 121.5, 117.7, 116.9, 99.3,
98.3, 77.0, 74.1, 73.4, 72.6, 72.4, 70.5, 67.6, 18.4, 18.3, 11.0;
IR (cmÀ 1): 3030, 2942, 2865, 2359, 1744, 1663, 1597, 1577,
1559, 1524, 1497, 1486, 1456, 1425, 1386, 1327, 1209, 1102,
1028; [α]20D = +186.2 (1.00, CHCl3); HRMS (TOF ES+) for
(M+H)+ C48H55N2O5Si+ (m/z): calc. 767.3880; found
767.3869.
1
next step. H NMR (400 MHz, CDCl3) δ 7.44–7.42 (m, 2H),
7.39–7.31 (m, 8H), 6.70 (s, 1H), 4.78 (d, J=10.9 Hz, 1H), 4.77
(d, J=11.5 Hz, 1H), 4.66 (d, J=10.9 Hz, 1H), 4.65 (d, J=
11.5 Hz, 1H), 4.23–4.16 (m, 1H), 4.13 (d, J=5.4 Hz, 1H), 3.64
(dd, J=7.4, 5.5 Hz, 1H), 1.38 (d, J=6.6 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 148.9, 137.9, 137.8, 128.7, 128.5, 128.3,
128.1, 128.0, 128.0, 79.8, 79.1, 74.3, 73.7, 72.5, 71.1, 17.0; IR
(cmÀ 1): 3089, 3063, 3030, 2975, 2936, 2873, 1734, 1718, 1624,
1497, 1454, 1380, 1365, 1350, 1236, 1208, 1166, 1138, 1100,
1072, 1055, 1029; [α]20D =-20.8 (1.00, CHCl3). 2-N-(quinolin-8-
yl)carbamoyl-3,4-di-O-benzyl-l-rhamnal (S2) was obtained
according to the literature:[11] in a sealed tube were added
Pd(OAc)2 (46.3 mg; 0.1 equiv.; 0.206 mmol), PPh3 (108.2 mg;
0.2 equiv.; 0.413 mmol), K2CO3 (570.2 mg; 2 equiv.;
4.126 mmol), Mo(CO)6 (2.3 g; 4.2 equiv.; 8.664 mmol), 8-
aminoquinoline (594.8 mg; 2 equiv.; 4.126 mmol), S1 (879 mg;
1 equiv.; 2.063 mmol) and dioxane (23 mL). The resulting
2-N-(quinolin-8-yl)carbamoyl-1-(cyclopropylethynyl)-3,4,6-
tri-O-benzyl-d–galactal (4b). 4b was obtained following the
general procedure of CÀ H functionalization: in a sealed tube
were added Na2CO3 (45.1 mg, 5 equiv., 0.426 mmol), (bromoe-
thynyl)cyclopropane (9.2 μL, 1.2 equiv., 0.102 mmol), 2-N-
(quinolin-8-yl)carbamoyl-3,4,6-tri-O-benzyl-d-galactal (50 mg,
1 equiv., 0.085 mmol) and toluene (0.43 mL). The resulting
mixture was stirred for 4 h at 140 C. Then Ni(OAc)2.4H2O
(4.2 mg, 20 mol%, 0.017 mmol) was added at room temperature
in the sealed tube. The resulting mixture was stirred at 140 C
overnight. The mixture was filtrated on celite with EtOAc and
then concentrated under vacuum. 4b was obtained after
purification on silica gel (eluent: Toluene/EtOAc 95:5) as
yellowish oil (12.5 mg; 0.019 mmol; 23%). 1H NMR
(400 MHz, CDCl3) δ 10.48 (s, 1H), 8.76 (dd, J=4.2, 1.7 Hz,
1H), 8.71 (dd, J=6.8, 2.1 Hz, 1H), 8.15 (dd, J=8.3, 1.6 Hz,
1H), 7.54–7.52 (m, 2H), 7.45–7.28 (m, 16H), 5.06 (d, J=
4.1 Hz, 1H), 4.85–4.81 (m, 2H), 4.67 (d, J=12.0 Hz, 1H), 4.63
(d, J=12.1 Hz, 1H), 4.62 (d, J=11.8 Hz, 1H), 4.59–4.55 (m,
1H), 4.37 (dd, J=11.3, 8.5 Hz, 1H), 4.16 (dd, J=5.9, 2.9 Hz,
1H), 4.08 (dd, J=11.3, 1.5 Hz, 1H), 3.50 (d, J=4.1 Hz, 1H),
0.93–0.88 (m, 1H), 0.44–0.26 (m, 4H); 13C NMR (101 MHz,
CDCl3) δ 168.0, 148.6, 139.4, 138.6, 138.5, 138.2, 137.7, 136.3,
134.2, 133.3, 129.1, 128.8, 128.6, 128.5, 128.2, 128.1, 128.0,
°
mixture was stirred at 80 C overnight. The mixture was
filtrated on celite with EtOAc and concentrated under vacuum.
S2 was purified on silica gel (eluent: Toluene/EtOAc 95:5) and
was washed with HCl (1 M) to remove excess of 8-aminoquino-
line and then with a saturated aqueous solution of NaHCO3. S2
was obtained as yellowish oil (727 mg; 1.513 mmol; 75%) and
was directly engaged in the next step. 1H NMR (400 MHz,
CDCl3) δ 10.62 (s, 1H), 8.84 (dd, J=7.6, 1.0 Hz, 1H), 8.34 (dd,
J=4.2, 1.6 Hz, 1H), 8.11 (dd, J=8.3, 1.5 Hz, 1H), 7.76 (s, 1H),
7.54 (t, J=7.9 Hz, 1H), 7.47 (dd, J=8.2, 0.9 Hz, 1H), 7.39–
7.28 (m, 11H), 5.14 (d, J=11.5 Hz, 1H), 4.74 (d, J=11.5 Hz,
1H), 4.68 (s, 2H), 4.58–4.55 (m, 2H), 3.79 (t, J=2.9 Hz, 1H),
1.43 (d, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 165.8,
153.5, 148.0, 138.9, 138.3, 137.7, 136.3, 135.4, 128.7, 128.5,
128.2, 128.1, 128.0, 127.7, 127.6, 127.4, 121.5, 121.2, 116.9,
107.9, 74.3, 73.8, 71.9, 71.5, 70.9, 16.3; IR (cmÀ 1): 2970, 1734,
1718, 1700, 1675, 1653, 1647, 1636, 1617, 1577, 1559, 1540,
1526, 1507, 1497, 1489, 1473, 1457, 1424, 1375, 1325, 1281,
1198, 1145, 1070, 1045, 1028; [α]20D = +0.23 (0.026, CHCl3);
°
°
+
HRMS (TOF ES+) for (M+H)+ C30H29N2O4 (m/z): calc.
481.2127; found 481.2126. 5a was obtained following the
general procedure of CÀ H functionalization: in a sealed tube
were added Na2CO3 (55 mg, 5 equiv., 0.520 mmol), bromo
Adv. Synth. Catal. 2021, 363, 1–12
7
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

RESEARCH ARTICLE
asc.wiley-vch.de
(triisopropylsilyl)acetylene (30.4 μL, 1.2 equiv., 0.125 mmol),
compound S2 (50 mg, 1 equiv., 0.104 mmol) and toluene
line and then with a saturated aqueous solution of NaHCO3. S2
was obtained as yellowish oil (727 mg; 1.513 mmol; 75%) and
was directly engaged in the next step. 1H NMR (400 MHz,
CDCl3) δ 10.62 (s, 1H), 8.84 (dd, J=7.6, 1.0 Hz, 1H), 8.34 (dd,
J=4.2, 1.6 Hz, 1H), 8.11 (dd, J=8.3, 1.5 Hz, 1H), 7.76 (s, 1H),
7.54 (t, J=7.9 Hz, 1H), 7.47 (dd, J=8.2, 0.9 Hz, 1H), 7.39–
7.28 (m, 11H), 5.14 (d, J=11.5 Hz, 1H), 4.74 (d, J=11.5 Hz,
1H), 4.68 (s, 2H), 4.58–4.55 (m, 2H), 3.79 (t, J=2.9 Hz, 1H),
1.43 (d, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 165.8,
153.5, 148.0, 138.9, 138.3, 137.7, 136.3, 135.4, 128.7, 128.5,
128.2, 128.1, 128.0, 127.7, 127.6, 127.4, 121.5, 121.2, 116.9,
107.9, 74.3, 73.8, 71.9, 71.5, 70.9, 16.3; IR (cmÀ 1): 2970, 1734,
1718, 1700, 1675, 1653, 1647, 1636, 1617, 1577, 1559, 1540,
1526, 1507, 1497, 1489, 1473, 1457, 1424, 1375, 1325, 1281,
1198, 1145, 1070, 1045, 1028; [α]20D = +0.23 (0.026, CHCl3);
°
(0.5 mL). The resulting mixture was stirred for 4 h at 140 C.
Then Ni(OAc)2.4H2O (5.2 mg, 20 mol%, 0.021 mmol) was
added at room temperature in the sealed tube. The resulting
°
mixture was stirred at 140 C overnight. The mixture was
filtrated on celite with EtOAc and then concentrated under
vacuum. 5a was obtained after purification on silica gel (eluent:
Toluene/EtOAc 95:5) as yellowish oil (20.3 mg; 0.031 mmol;
1
30%). H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H), 8.76 (dd,
J=7.4, 1.4 Hz, 1H), 8.64 (dd, J=4.2, 1.6 Hz, 1H), 8.06 (dd,
J=8.3, 1.6 Hz, 1H), 7.49–7.45 (m, 1H), 7.42 (dd, J=8.3,
1.5 Hz, 1H), 7.33 (dd, J=8.3, 4.2 Hz, 1H), 7.30–7.28 (m, 2H),
7.24–7.18 (m, 3H), 7.16–7.13 (m, 2H), 7.08–7.06 (m, 3H),
4.73–4.67 (m, 3H), 4.57 (d, J=11.2 Hz, 1H), 4.55 (d, J=
11.8 Hz, 1H), 4.31–4.25 (m, 1H), 3.59 (dd, J=5.8, 4.7 Hz, 1H),
1.39 (d, J=6.7 Hz, 3H), 0.74–0.68 (m, 21H); 13C NMR
(101 MHz, CDCl3) δ 165.5, 148.3, 138.9, 138.4, 137.9, 136.2,
135.0, 128.6, 128.3, 128.1, 128.0, 128.0, 127.9, 127.6, 127.5,
121.6, 121.5, 117.8, 117.0, 98.8, 98.5, 77.4, 75.0, 74.6, 73.6,
73.0, 18.4, 18.3, 16.9, 11.1; IR (cmÀ 1): 2926, 2866, 2360, 2339,
1734, 1662, 1597, 1577, 1559, 1525, 1487, 1457, 1425, 1383,
1340, 1327, 1216, 1137, 1092, 1072, 1028; [α]20D =-157.1
(1.00, CHCl3); HRMS (TOF ES+) for (M+H)+
C41H49N2O4Si+ (m/z): calc. 661.3462; found 661.3461.
+
HRMS (TOF ES+) for (M+H)+ C30H29N2O4 (m/z): calc.
481.2127; found 481.2126. 5b was obtained following the
general procedure of CÀ H functionalization: in a sealed tube
were added Na2CO3 (55 mg, 5 equiv., 0.520 mmol), (bromoe-
thynyl)triphenylsilane (45.4 mg, 1.2 equiv., 0.125 mmol), com-
pound S2 (50 mg, 1 equiv., 0.104 mmol) and toluene (0.5 mL).
°
The resulting mixture was stirred for 4 h at 140 C. Then
Ni(OAc)2.4H2O (5.2 mg, 20 mol%, 0.021 mmol) was added at
room temperature in the sealed tube. The resulting mixture was
°
stirred at 140 C overnight. The mixture was filtrated on celite
with EtOAc and then concentrated under vacuum. 5b was
2-N-(quinolin-8-yl)carbamoyl-1-((triphenylsilyl)ethynyl)-3,4-
O-benzyl-l–rhamnal (5b). 3,4-di-O-benzyl-l-rhamnal was
prepared according to the literature.[20] 2-Iodo-3,4-di-O-benzyl-
l-rhamnal (S1) was synthesized following the described
obtained after purification on silica gel (eluent: Toluene/EtOAc
1
95:5) as yellowish oil (16.8 mg; 0.022 mmol; 21%). H NMR
(400 MHz, CDCl3) δ 10.64 (s, 1H), 8.80 (dd, J=7.7, 0.9 Hz,
1H), 7.92 (dd, J=4.2, 1.6 Hz, 1H), 7.86 (dd, J=8.3, 1.5 Hz,
1H), 7.56 (dd, J=7.9, 1.4 Hz, 2H), 7.46 (t, J=8.0 Hz, 1H),
7.38–7.35 (m, 2H), 7.32–7.29 (m, 9H), 7.18–7.15 (m, 5H), 7.09
(dd, J=5.0, 2.0 Hz, 3H), 7.04–7.00 (m, 6H), 4.80 (dd, J=4.1,
0.9 Hz, 1H), 4.73 (d, J=11.2 Hz, 1H), 4.67 (d, J=11.8 Hz,
1H), 4.57 (d, J=11.4 Hz, 1H), 4.54 (d, J=11.9 Hz, 1H), 4.36–
4.30 (m, 1H), 3.62–3.59 (m, 1H), 1.40 (d, J=6.8 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 164.9, 148.2, 138.6, 138.5, 138.4,
137.8, 135.8, 135.7, 135.5, 135.3, 135.2, 135.1, 134.9, 132.2,
130.2, 129.9, 128.7, 128.3, 128.2, 128.1, 128.1, 128.0, 127.9,
127.8, 127.6, 127.3, 121.7, 121.4, 118.5, 116.8, 100.4, 97.5,
77.0, 75.2, 73.7, 73.6, 72.7, 16.9; IR (cmÀ 1): 2920, 2865, 2360,
2343, 1734, 1718, 1684, 1669, 1654, 1647, 1636, 1617, 1597,
1578, 1559, 1497, 1457, 1429, 1375, 1340, 1328, 1262, 1217,
1135, 1115, 1071, 1028; [α]20D =-143.4 (0.49, CHCl3); HRMS
(TOF ES+) for (M+H)+ C50H43N2O4Si+ (m/z): calc.
763.2992; found 763.2994.
procedure:[18]
3,4-di-O-benzyl-l-rhamnal
(1 g,
1 equiv.,
3.22 mmol) was dissolved in dry acetonitrile (22 mL) under
°
argon and the resulting mixture was heated to 80 C. At this
temperature,
N-iodosuccinimide
(870 mg,
1.2 equiv.,
3.87 mmol) and silver nitrate (109 mg, 20 mol%, 0.64 mmol)
°
were added. The resulting mixture was stirred at 80 C for 2 h.
The mixture was filtrated on celite with EtOAc and concen-
trated with silica. The obtained crude was purified on silica gel
(eluent: Cyclo/EtOAc 95:5) and furnished S1 as a colorless oil
(942 mg, 2.16 mmol, 67%) which was directly engaged in the
1
next step. H NMR (400 MHz, CDCl3) δ 7.44–7.42 (m, 2H),
7.39–7.31 (m, 8H), 6.70 (s, 1H), 4.78 (d, J=10.9 Hz, 1H), 4.77
(d, J=11.5 Hz, 1H), 4.66 (d, J=10.9 Hz, 1H), 4.65 (d, J=
11.5 Hz, 1H), 4.23–4.16 (m, 1H), 4.13 (d, J=5.4 Hz, 1H), 3.64
(dd, J=7.4, 5.5 Hz, 1H), 1.38 (d, J=6.6 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 148.9, 137.9, 137.8, 128.7, 128.5, 128.3,
128.1, 128.0, 128.0, 79.8, 79.1, 74.3, 73.7, 72.5, 71.1, 17.0; IR
(cmÀ 1): 3089, 3063, 3030, 2975, 2936, 2873, 1734, 1718, 1624,
1497, 1454, 1380, 1365, 1350, 1236, 1208, 1166, 1138, 1100,
1072, 1055, 1029; [α]20D =-20.8 (1.00, CHCl3). 2-N-(quinolin-8-
yl)carbamoyl-3,4-di-O-benzyl-l-rhamnal (S2) was obtained
according to the literature:[11] in a sealed tube were added
Pd(OAc)2 (46.3 mg; 0.1 equiv.; 0.206 mmol), PPh3 (108.2 mg;
0.2 equiv.; 0.413 mmol), K2CO3 (570.2 mg; 2 equiv.;
4.126 mmol), Mo(CO)6 (2.3 g; 4.2 equiv.; 8.664 mmol), 8-
aminoquinoline (594.8 mg; 2 equiv.; 4.126 mmol), S1 (879 mg;
1 equiv.; 2.063 mmol) and dioxane (23 mL). The resulting
2-N-tert-butoxycarbonyl-N-((quinolin-8-yl)carbamoyl)-1-
((triisopropylsilyl)ethynyl)-3,4,6-tri-O-benzyl-d–glucal (6). 6
was obtained according to the literature:[21] compound 2a
(408 mg, 1 equiv., 0.532 mmol) was dissolved in dry
acetonitrile (13 mL) under argon. Then DMAP (32.5 mg,
0.5 equiv., 0.266 mmol) and Boc2O (1.2 g, 10 equiv.,
5.319 mmol) were added. The resulting mixture was stirred at
°
65 C for 3 h under argon. DMAP (32.5 mg, 0.5 equiv.,
0.266 mmol) and Boc2O (1.2 g, 10 equiv., 5.319 mmol) were
°
added one more time. The reaction was stirred again at 65 C
°
mixture was stirred at 80 C overnight. The mixture was
for 3 h more. The mixture was concentrated under vacuum and
6 was obtained after purification on silica gel (eluent: Toluene/
EtOAc 95:5) as yellowish oil (364.4 mg; 0.420 mmol; 79%). 1H
NMR (400 MHz, CDCl3) δ 8.67 (d, J=3.9 Hz, 1H), 8.06 (dd,
filtrated on celite with EtOAc and concentrated under vacuum.
S2 was purified on silica gel (eluent: Toluene/EtOAc 95:5) and
was washed with HCl (1 M) to remove excess of 8-aminoquino-
Adv. Synth. Catal. 2021, 363, 1–12
8
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

RESEARCH ARTICLE
asc.wiley-vch.de
J=8.3, 1.3 Hz, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.45–7.41 (m,
1H), 7.35–7.34 (m, 2H), 7.31–7.26 (m, 6H), 7.24–7.19 (m, 7H),
7.15 (d, J=7.7 Hz, 2H), 4.89 (d, J=10.9 Hz, 1H), 4.57 (d, J=
12.0 Hz, 2H), 4.53 (d, J=11.8 Hz, 2H), 4.43–4.31 (m, 3H),
3.96–3.86 (m, 2H), 3.77 (dd, J=11.2, 3.2 Hz, 1H), 1.26 (s, 9H),
1.07–1.06 (m, 21H); 13C NMR (101 MHz, CDCl3) δ 152.6,
150.1, 144.5, 138.9, 138.5, 138.0, 137.1, 136.0, 129.2, 129.0,
128.9, 128.5, 128.4, 128.3, 128.2, 128.2, 128.0, 127.8, 127.8,
127.6, 127.4, 126.1, 125.4, 121.5, 99.2, 82.7, 81.2, 78.2, 73.6,
73.5, 72.9, 72.8, 68.2, 27.9, 18.8, 18.8, 11.4; IR (cmÀ 1): 2942,
2865, 2360, 2344, 1743, 1718, 1696, 1684, 1669, 1654, 1647,
1636, 1617, 1577, 1559, 1540, 1522, 1507, 1498, 1490, 1472,
1457, 1437, 1368, 1271, 1217, 1157, 1117, 1069, 1028;
[α]20D =-44.5 (0.45, CHCl3); HRMS (TOF ES+) for (M+H)+
C53H63N2O7Si+ (m/z): calc. 867.4405; found 867.4409.
8.0 Hz, 1H), 4.91–4.42 (m, 8H), 4.33–4.22 (m, 3H), 4.10–3.92
(m, 2H), 3.79–3.76 (m, 1H), 3.67 (s, 3H), 1.89–1.84 (m, 2H),
1.81–1.74 (m, 1H), 1.66–1.55 (m, 3H), 1.40 (s, 9H), 1.16–1.10
(m, 9H); 13C NMR (101 MHz, CDCl3) δ 173.1, 170.6, 155.5,
152.4, 149.6, 144.3, 138.7, 138.5, 137.9, 137.0, 136.1, 129.3,
128.8, 128.5, 128.4, 128.3, 128.1, 127.88, 127.8, 127.6, 127.6,
126.5, 121.3, 109.9, 82.1, 80.1, 77.4, 73.6, 73.2, 72.5, 72.3,
68.1, 53.1, 52.6, 50.0, 29.9, 29.8, 28.4, 27.6, 22.4; IR (cmÀ 1):
3063, 3033, 2929, 2866, 1743, 1717, 1684, 1670, 1654, 1636,
1540, 1521, 1517, 1507, 1498, 1473, 1456, 1437, 1391, 1368,
1323, 1273, 1254, 1204, 1160, 1121, 1091, 1072, 1028;
[α]20D =-62.1 (1.00, CHCl3); HRMS (TOF ES+) for (M+H)+
+
C56H65N6O11 (m/z): calc. 997.4711; found 997.4712.
2-N-tert-butoxycarbonyl-N-((quinolin-8-yl)carbamoyl)-1-(1-
(((2R,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-meth-
2-N-tert-butoxycarbonyl-N-((quinolin-8-yl)carbamoyl)-1-(1-
benzyl-1H-1,2,3-triazol-4-yl)-3,4,6-tri-O-benzyl-d–glucal
(7a). 7a was obtained following the general procedure of the
click reaction: compound 6 (474 mg, 1 equiv., 0.577 mmol) was
dissolved in dry THF (6.3 mL) under argon. Then triethylamine
(241 μL, 3 equiv., 1.730 mmol) and TBAF (0.87 mL, 1.5 equiv.,
0.865 mmol) were added and the reaction was stirred at room
temperature. The color of the reaction mixture changed in
purple, and after that CuI (55 mg, 0.5 equiv., 0.288 mmol) and
benzyl azide (108 μL, 1.5 equiv., 0.865 mmol) were added. The
oxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-
3,4,6-tri-O-benzyl-d–glucal (7c). 7c was obtained following
the general procedure of the click reaction: compound 6
(50.4 mg, 1 equiv., 0.058 mmol) was dissolved in dry THF
(0.64 mL) under argon. Then triethylamine (24 μL, 3 equiv.,
0.173 mmol) and TBAF (86 μL, 1.5 equiv., 0. 86 mmol) were
added and the reaction was stirred at room temperature. The
color of the reaction mixture changed in purple, and after that
CuI (5.5 mg, 0.5 equiv., 0.029 mmol) and methyl 6-azido-6-
deoxy-2,3,4-tri-O-benzyl-α-d-glucopyranoside
(42.2 mg,
°
reaction was stirred at 40 C overnight. The mixture was
1.5 equiv., 0.086 mmol) were added. The reaction was stirred at
°
concentrated under vacuum and 7a was obtained after
purification on silica gel (eluent: Cyclo/EtOAc 7:3) as yellowish
oil (332 mg; 0.393 mmol; 72%). 1H NMR (400 MHz,
(CD3)2CO) δ 8.73 (d, J=3.8 Hz, 1H), 8.34 (d, J=8.2 Hz, 1H),
8.20 (s, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.63–7.59 (m, 1H), 7.48
(dd, J=8.4, 4.3 Hz, 1H), 7.44–7.24 (m, 21H), 5.70 (s, 2H),
4.98 (d, J=10.8 Hz, 1H), 4.76–4.53 (m, 8H), 4.09 (s, 1H), 3.87
(dd, J=11.2, 3.8 Hz, 1H), 0.98 (s, 9H); 13C NMR (101 MHz,
(CD3)2CO) δ 153.0, 150.7, 145.7, 145.5, 143.7, 140.1, 139.8,
139.3, 138.6, 136.9, 136.7, 129.7, 129.5, 129.2, 129.1, 129.0,
129.0, 128.8, 128.6, 128.3, 128.3, 128.1, 128.0, 127.1, 125.1,
122.3, 109.9, 81.6, 77.7, 74.3, 73.9, 72.7, 72.1, 68.9, 54.3,
27.6.; IR (cmÀ 1): 3064, 3030, 3008, 2979, 2929, 2865, 1743,
1684, 1669, 1654, 1636, 1617, 1456, 1437, 1388, 1368, 1323,
1273, 1254, 1217, 1155, 1120, 1092, 1071, 1046, 1028;
[α]20D =-56.8 (1.00, CHCl3); HRMS (TOF ES+) for (M+H)+
40 C overnight. The mixture was concentrated under vacuum
and 7c was obtained after purification on silica gel (eluent:
Toluene/EtOAc 9:1 then 85:15) as yellowish oil (50.1 mg;
1
0.042 mmol; 73%). H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H),
8.01 (d, J=7.6 Hz, 1H), 7.64–7.57 (m, 1H), 7.50–7.44 (m, 1H),
7.33–7.20 (m, 33H), 4.94–4.91 (m, 2H), 4.84 (d, J=10.8 Hz,
1H), 4.79–4.74 (m, 2H), 4.70–4.62 (m, 4H), 4.59–4.38 (m, 9H),
4.12–3.90 (m, 4H), 3.80–3.79 (m, 1H), 3.33 (dd, J=9.5,
3.0 Hz, 1H), 3.10–3.08 (m, 3H), 1.21–1.13 (m, 9H); 13C NMR
(101 MHz, (CDCl3) δ 170.6, 152.5, 149.6, 144.3, 142.1, 138.6,
138.4, 138.2, 138.0, 137.9, 136.9, 136.1, 136.0, 134.6, 129.9,
129.3, 129.1, 129.1, 128.7, 128.7, 128.6, 128.6, 128.5, 128.5,
128.4, 128.4, 128.3, 128.3, 128.1, 128.1, 128.0, 127.9, 127.8,
127.7, 127.7, 127.1, 126.4, 121.3, 110.1, 98.0, 82.4, 82.0, 79.9,
79.2, 78.0, 75.7, 75.1, 73.5, 73.3, 72.6, 72.3, 69.0, 67.9, 65.4,
55.6, 50.6, 27.6; IR (cmÀ 1): 3064, 3030, 3009, 2925, 1743,
1684, 1670, 1654, 1507, 1497, 1425, 1419, 1389, 1369, 1323,
1273, 1254, 1217, 1156, 1091, 1071, 1028; [α]20D =-32.6 (1.00,
+
C51H50N5O7 (m/z): calc. 844.3710; found 844.3731.
2-N-tert-butoxycarbonyl-N-((quinolin-8-yl)carbamoyl)-1-
(methyl (S)-2-((tert-butoxycarbonyl)amino)-6-(1H-1,2,3-tria-
zol-4-yl)hexanoyl)-3,4,6-tri-O-benzyl-d–glucal (7b). 7b was
obtained following the general procedure of the click reaction:
compound 6 (51.6 mg, 1 equiv., 0.060 mmol) was dissolved in
dry THF (0.63 mL) under argon. Then triethylamine (24 μL,
3 equiv., 0.173 mmol) and TBAF (86.5 μL, 1.5 equiv.,
0.087 mmol) were added and the reaction was stirred at room
temperature. The color of the reaction mixture changed in
purple, and after that CuI (5.6 mg, 0.5 equiv., 0.029 mmol) and
Boc-l-Lys(N3)-OMe (24.8 mg, 1.5 equiv., 0.087 mmol) were
+
CHCl3); HRMS (TOF ES+) for (M+H)+ C72H74N5O12 (m/z):
calc. 1200.5334; found 1200.5343.
2-N-tert-butoxycarbonyl-N-((quinolin-8-yl)carbamoyl)-1-(1-
(13-oxo-17-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]
imidazol-4-yl)-3,6,9-trioxa-12-azaheptadecyl)-1H-1,2,3-tria-
zol-4-yl)-3,4,6-tri-O-benzyl-d–glucal (7d). 7d was obtained
following the general procedure of the click reaction: compound
6 (49.6 mg, 1 equiv., 0.058 mmol) was dissolved in dry THF
(0.64 mL) under argon. Then triethylamine (24 μL, 3 equiv.,
0.173 mmol) and TBAF (86 μL, 1.5 equiv., 0.86 mmol) were
added and the reaction was stirred at room temperature. The
color of the reaction mixture changed in purple, and after that
CuI (5.5 mg, 0.5 equiv., 0.029 mmol) and Biotin-PEG3-azide
(38.4 mg, 1.5 equiv., 0.086 mmol) were added. The reaction
°
added. The reaction was stirred at 40 C overnight. The mixture
was concentrated under vacuum and 7b was obtained after
purification on silica gel (eluent: Cyclo/EtOAc 5:5) as yellowish
oil (23.4 mg; 0.023 mmol; 39%). 1H NMR (400 MHz, CDCl3) δ
8.58 (s, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.67 (dd, J=5.3, 1.0 Hz,
1H), 7.34–7.32 (m, 2H), 7.30–7.18 (m, 17H), 5.00 (d, J=
°
was stirred at 40 C overnight. The mixture was concentrated
under vacuum and 7d was obtained after purification on silica
Adv. Synth. Catal. 2021, 363, 1–12
9
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

RESEARCH ARTICLE
asc.wiley-vch.de
gel (eluent: Toluene/EtOAc 98:2 then 9:1) as yellowish oil
(37.9 mg; 0.033 mmol; 57%). H NMR (400 MHz, CDCl3) δ
124.7, 121.6, 121.5, 116.7, 110.4, 77.0, 73.6, 73.4, 72.5, 72.3,
72.2, 67.6, 54.1; IR (cmÀ 1): 1734, 1718, 1684, 1669, 1663,
1654, 1648, 1570, 1559, 1539, 1522, 1508, 1497, 1486, 1456,
1437, 1425, 1387, 1340, 1327, 1261, 1228, 1206, 1163, 1099,
1071, 1045, 1028, 1003; [α]20D = +71.6 (1.00, CHCl3); HRMS
1
8.66 (s, 1H), 8.32–8.10 (m, 2H), 7.73 (d, J=7.5 Hz, 1H), 7.56–
7.07 (m, 18H), 6.71 (s, 1H), 6.23 (s, 1H), 5.32–5.29 (m, 1H),
5.04–4.54 (m, 9H), 4.41–4.38 (m, 1H), 4.23–4.20 (m, 1H),
4.09–3.82 (m, 4H), 3.66–3.46 (m, 10H), 3.38–3.30 (m, 3H),
3.07 (dd, J=11.8, 7.2 Hz, 1H), 2.82 (dd, J=12.7, 4.7 Hz, 1H),
2.66 (d, J=12.8 Hz, 1H), 2.15 (t, J=7.4 Hz, 2H), 2.08–1.94
(m, 1H), 1.69–1.58 (m, 4H), 1.48–1.43 (m, 1H), 1.40–1.35 (m,
1H), 1.25–1.14 (m, 9H); 13C NMR (101 MHz, CDCl3) δ 173.5,
170.5, 163.8, 152.4, 149.8, 144.3, 138.7, 138.4, 137.9, 137.0,
136.1, 129.2, 128.8, 128.5, 128.5, 128.3, 128.1, 127.9, 127.7,
127.6, 126.5, 121.4, 110.4, 82.2, 77.4, 73.6, 73.3, 72.6, 72.3,
70.8, 70.5, 70.4, 70.1, 69.9, 69.5, 68.1, 61.8, 60.2, 59.2, 55.5,
50.4, 40.6, 39.2, 35.8, 28.2, 28.1, 27.6, 25.7; IR (cmÀ 1): 3007,
2930, 2866, 1744, 1701, 1654, 1559, 1540, 1522, 1507, 1498,
1472, 1456, 1388, 1369, 1324, 1272, 1254, 1215, 1153, 1121,
1072, 1028; [α]20D =-52.3 (1.00, CHCl3); HRMS (TOF ES+)
for (M+H)+ C62H75N8O12S+ (m/z): calc. 1155.5225; found
1155.5208.
+
(TOF ES+) for (M+H)+ C46H42N5O5 (m/z): calc. 744.3186;
found 744.3189.
Acknowledgements
A.F. thanks the Agence Nationale de la Recherche for financial
support (SuCH_Fun, JCJC ANR-18-CE07-0030-01).
References
[1] a) A. Varki, Glycobiology 1993, 3, 97–130; b) P. M.
Rudd, T. Elliott, P. Cresswell, I. A. Wilson, R. A. Dwek,
Science 2001, 291, 2370–2376; c) P. H. Seeberger, D. B.
Werz, Nature 2007, 446, 1046–1051; d) D. P. Galonic,
D. Y. Gin, Nature 2007, 446, 1000–1007.
[2] a) T. Bililign, B. R. Griffith, J. S. Thorson, Nat. Prod.
Rep. 2005, 22, 742–760; b) F. Nicotra, Top. Curr. Chem.
1997, 187, 55–83; c) E. De Clercq, J. Med. Chem. 2016,
59, 2301–2311; d) L.-Q. Wan, X. Zhang, Y. Zou, R. Shi,
J.-G. Cao, S.-Y. Xu, L.-F. Deng, L. Zhou, Y. Gong, X.
Shu, G. Y. Lee, H. Ren, L. Dai, S. Qi, K. N. Houk, D.
Niu, J. Am. Chem. Soc. 2021, 143, 11919–11926; e) W.
Shang, S.-N. Su, R. Shi, Z.-D. Mou, G.-Q. Yu, X. Zhang,
D. Niu, Angew. Chem. Int. Ed. 2021, 60, 385–390;
Angew. Chem. 2021, 133, 389–394.
2-N-(pyrrolidinyl)carbamoyl-1-(1-benzyl-1H-1,2,3-triazol-4-
yl)-3,4,6-tri-O-benzyl-d–glucal (8) and 2-N-(quinolin-8-yl)
carbamoyl-1-(1-benzyl-1H-1,2,3-triazol-4-yl)-3,4,6-tri-O-
benzyl-d–glucal (9). 8 and 9 were obtained with the following
procedure: compound 7a (22.5 mg, 1 equiv., 0.027 mmol) was
dissolved in toluene (0.1 mL) under argon. Then pyrrolidine
(4.1 μL, 1.5 equiv., 0.049 mmol) was added and the reaction
°
was stirred at 65 C overnight. The mixture was concentrated
under vacuum and 8 and 9 were obtained after purification on
silica gel (eluent: Cyclo/EtOAc 5:5 to have 9 and then 0:100 to
have 8) as yellowish oils (8: 6.2 mg; 0.009 mmol; 35% and 9:
1
8.1 mg; 0.011 mmol; 41%). 8 H NMR (400 MHz, CDCl3) δ
[3] K. F. Suazo, K.-Y. Park, M. D. Distefano, Chem. Rev.
2021, DOI: 10.1021/acs.chemrev.0c01108.
7.57 (s, 1H), 7.35–7.18 (m, 20H), 5.54 (d, J=14.8 Hz, 1H),
5.41 (d, J=14.8 Hz, 1H), 4.76 (d, J=11.7 Hz, 1H), 4.64 (d, J=
11.7 Hz, 1H), 4.60–4.55 (m, 3H), 4.51 (d, J=12.2 Hz, 1H),
4.42 (dd, J=9.9, 5.3 Hz, 1H), 4.01–3.98 (m, 1H), 3.87 (dd, J=
10.7, 5.4 Hz, 1H), 3.77–3.74 (m, 1H), 3.47–3.40 (m, 2H), 3.35–
3.28 (m, 1H), 2.91 (d, J=7.2 Hz, 1H), 1.74–1.52 (m, 4H),
1.27–1.23 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 167.0,
142.7, 138.4, 138.0, 138.0, 134.6, 129.2, 128.9, 128.6, 128.4,
128.4, 128.2, 128.0, 127.9, 127.8, 127.7, 122.9, 109.9, 76.9,
73.6, 73.4, 73.1, 67.6, 54.2, 47.5, 45.7, 25.6, 24.4; IR (cmÀ 1):
3029, 2971, 2926, 2855, 1734, 1718, 1706, 1700, 1684, 1669,
1663, 1653, 1647, 1636, 1617, 1577, 1570, 1559, 1550, 1540,
1534, 1522, 1517, 1507, 1497, 1490, 1473, 1457, 1437, 1419,
1395, 1387, 1374, 1363, 1340, 1229, 1217, 1091, 1028;
[α]20D = +19.7 (0.32, CHCl3); HRMS (TOF ES+) for (M+
[4] a) V. K. Tiwari, B. B. Mishra, K. B. Mishra, N. Mishra,
A. S. Singh, X. Chen, Chem. Rev. 2016, 116, 3086–3240;
b) S. Somesh, K. Madhuri, Org. Chem. 2016, 12, 104;
c) K. Thakur, N. K. Khare, Carbohydr. Res. 2019, 484,
107775–107780; d) A. K. Agrahari, P. Bose, M. K.
Jaiswal, S. Rajkhowa, A. S. Singh, S. Hotha, N. Mishra,
V. K. Tiwari, Chem. Rev. 2021, DOI: 10.1021/acs.chem-
rev.0c00920.
[5] Selected articles: a) S. Nerella, S. Kankala, B. Gavaji,
Nat. Prod. Res. 2021, 35, 9–16; b) H. Song, S. J. Allison,
V. Brabec, H. E. Bridgewater, J. Kasparkova, H. Kostr-
hunova, V. Novohradsky, R. M. Phillips, J. Pracharova,
N. J. Rogers, S. L. Shepherd, P. Scott, Angew. Chem. Int.
Ed. 2020, 59, 14677–14685; Angew. Chem. 2020, 132,
14785–14793; c) L. Li, K.-C. Chang, Y. Zhou, B. Shieh,
J. Ponder, A. D. Abraham, H. Ali, A. Snow, J. M.
Petrash, D. V. LaBarbera, J. Med. Chem. 2014, 57, 71–
77; d) B. H. M. Kuijpers, S. Groothuys, A. C. Soede, P.
Laverman, O. C. Boerman, F. L. van Delft, F. P. J. T.
Rutjes, Bioconjugate Chem. 2007, 18, 1847–1854; e) Y.
Chang, C. Hou, J. Ren, X. Xin, Y. Pei, Y. Lu, S. Cao, Z.
Pei, Chem. Commun. 2016, 52, 9578–9581.
H)+ C41H43N4O5 (m/z): calc. 671.3233; found 671.3235. 9 H
NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 8.75 (dd, J=7.4,
1.5 Hz, 1H), 8.42 (dd, J=4.2, 1.6 Hz, 1H), 8.08 (dd, J=8.3,
1.6 Hz, 1H), 7.66 (s, 1H), 7.52–7.48 (m, 1H), 7.45 (dd, J=8.3,
1.6 Hz, 1H), 7.32 (dd, J=8.3, 4.3 Hz, 1H), 7.30–7.23 (m, 11H),
7.17 (dd, J=7.3, 2.2 Hz, 2H), 7.12–7.09 (m, 5H), 6.96 (d, J=
7.4 Hz, 2H), 5.33 (d, J=14.8 Hz, 1H), 5.25 (d, J=14.8 Hz,
1H), 4.72–4.69 (m, 1H), 4.68 (d, J=12.3 Hz, 1H), 4.63–4.57
(m, 3H), 4.09–4.07 (m, 1H), 3.95 (dd, J=10.5, 6.0 Hz, 1H),
3.87 (dd, J=10.5, 5.3 Hz, 1H), 3.32–3.23 (m, 3H); 13C NMR
(101 MHz, CDCl3) δ 166.2, 148.1, 146.9, 142.0, 138.6, 138.2,
137.8, 136.1, 135.0, 134.1, 129.0, 128.7, 128.6, 128.5, 128.2,
128.1, 128.0, 128.0, 128.0, 127.8, 127.8, 127.7, 127.6, 127.5,
+
1
[6] Selected articles: a) D. Crich, F. Yang, Angew. Chem. Int.
Ed. 2009, 48, 8896–8899; Angew. Chem. 2009, 121,
9058–9061; b) V. Neto, R. Granet, P. Krausz, Tetrahe-
Adv. Synth. Catal. 2021, 363, 1–12
10
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

RESEARCH ARTICLE
asc.wiley-vch.de
dron 2010, 66, 4633–4646; c) G. Yu, J. Li, W. Yu, C. [10] a) M. B. Tatina, A. K. Kusunuru, S. K. Yousuf, D.
Han, Z. Mao, C. Gao, F. Huang, Adv. Mater. 2013, 25,
6373–6379; d) B. P. Krishnan, S. Ramakrishnan, K. M.
Sureshan, Chem. Commun. 2013, 49, 1494–1496; e) I.
Mukherjee, Org. Biomol. Chem. 2014, 12, 7900–7903;
b) C. Ayed, S. Palmier, N. Lubin-Germain, J. Uziel, J.
Augé, Carbohydr. Res. 2010, 345, 2566–2570.
Glassford, C. N. Teijaro, S. S. Daher, A. Weil, M. C. [11] M. de Robichon, A. Bordessa, M. Malinowski, J. Uziel,
Small, S. K. Redhu, D. J. Colussi, M. A. Jacobson, W. E.
Childers, B. Buttaro, A. W. Nicholson, A. D. MacKer-
N. Lubin-Germain, A. Ferry, Chem. Commun. 2019, 55,
11806–11808.
ell Jr., B. S. Cooperman, R. B. Andrade, J. Am. Chem. [12] J. Ghouilem, M. de Robichon, F. Le Bideau, A. Ferry, S.
Soc. 2016, 138, 3136–3144. Messaoudi, Chem. Eur. J. 2021, 27, 491–511.
[7] Selected articles: a) F. Pertici, R. J. Pieters, Chem. [13] J. Yi, L. Yang, C. Xia, F. Li, J. Org. Chem. 2015, 80,
Commun. 2012, 48, 4008–4010; b) M. Lo Conte, D. 6213–6221.
Grotto, A. Chambery, A. Dondonia, A. Marra, Chem. [14] L. D. Caspers, B. J. Nachtsheim, Chem. Asian J. 2018,
Commun. 2011, 47, 1240–1242; c) S. I. van Kasteren, 10, 1225–1231.
H. B. Kramer, H. H. Jensen, S . Campbell, J. Kirkpatrick, [15] Selected articles: a) A. Mondal, M. van Gemmeren,
N. J. Oldham, D. C. Anthony, B. G. Davis, Nature 2007,
446, 1105–1109; d) L. Moni, A. Ciogli, I. D’Acquarica,
A. Dondoni, F. Gasparrini, A. Marra, Chem. Eur. J. 2010,
16, 5712–5722; e) F. Pertici, N. J. de Mol, J. Kemmink,
R. J. Pieters, Chem. Eur. J. 2013, 19, 16923–16927;
f) B. H. M. Kuijpers, S. Groothuys, A. B. R. Keereweer,
P. J. L. M. Quaedflieg, R. H. Blaauw, F. L. van Delft,
F. P. J. T. Rutjes, Org. Lett. 2004, 6, 3123–3126; g) G.
Yu, A. C. Vicini, R. J. Pieters, J. Org. Chem. 2019, 84,
2470–2488.
Angew. Chem. Int. Ed. 2020, 60, 742–746; b) B. S.
Schreib, M. Fadel, E. M. Carreira, Angew. Chem. Int. Ed.
2020, 59, 7818–7822; Angew. Chem. 2020, 132, 7892–
7896; c) A. Mondal, H. Chen, L. Flämig, P. Wedi, M.
van Gemmeren, J. Am. Chem. Soc. 2019, 141, 18662–
18667; d) C. Feng, T.-P. Loh, Angew. Chem. Int. Ed.
2014, 53, 2722–2726; Angew. Chem. 2014, 126, 2760–
2764; e) Z. Ruan, N. Sauermann, E. Manoni, L.
Ackermann, Angew. Chem. Int. Ed. 2017, 56, 3172–
3176; Angew. Chem. 2017, 129, 3220–3224; f) M.
Shang, H.-L. Wang, S.-Z. Sun, H.-X. Dai, J.-Q. Yu, J.
Am. Chem. Soc. 2014, 136, 11590–11593.
[8] Selected articles: a) N. Lubin-Germain, A. Hallonet, F.
Huguenot, S. Palmier, J. Uziel, J. Augé, Org. Lett. 2007,
18, 3679–3682; b) N. Lubin-Germain, J.-P. Baltaze, A. [16] Selected articles: a) Z. Ruan, S. Lackner, L. Ackermann,
Coste, A. Hallonet, H. Lauréano, G. Legrave, J. Uziel, J.
Augé, Org. Lett. 2008, 5, 725–728; c) J. L. Koviach,
M. D. Chappell, R. L. Halcomb, J. Org. Chem. 2001, 66,
2318–2326; d) J. W. Lane, R. L. Halcomb, J. Org. Chem.
2003, 68, 1348–1357; e) M. A. Leeuwenburgh, C. C. M.
Appeldoorn, P. A. V. van Hooft, H. S. Overkleeft, G. A.
van der Marel, J. H. van Boom, Eur. J. Org. Chem. 2000,
ACS Catal. 2016, 6, 4690–4693; b) J. Yi, L. Yang, C.
Xia, F. Li, J. Org. Chem. 2015, 80, 6213–6221; c) N.
Matsuyama, M. Kitahara, K. Hirano, T. Satoh, M. Miura,
Org. Lett. 2010, 12, 2358–2361; d) N. Matsuyama, K.
Hirano, T. Satoh, M. Miura, Org. Lett. 2009, 11, 4156–
4159; e) S. M. Khake, V. Soni, R. G. Gonnade, B. Punji,
Chem. Eur. J. 2017, 23, 2907–2914.
2000, 873–877; f) H. Yamada, M. Adachi, M. Isobe, T. [17] L. S. Fitzgerald, M. L. O’Duill, Chem. Eur. J. 2021,
Nishikawa, Chem. Asian J. 2013, 8, 1428–1435; g) S. DOI: 10.1002/chem.202100093.
Wagschal, J. Guilbaud, P. Rabet, V. Farina, S. Lemaire, J. [18] S. Dharuman, Y. D. Vankar, Org. Lett. 2014, 16, 1172–
Org. Chem. 2015, 80, 9328–9335; h) S. P. Allwein, J. M. 1175.
Cox, B. E. Howard, H. W. Johnson, J. D. Rainier, [19] a) S. Nicolai, J. Waser, Org. Lett. 2011, 13, 6324–6327;
Tetrahedron 2002, 58, 1997–2009; i) M. A. Leeuwen-
burgh, H. S. Overkleeft, G. A. van der Marel, J. H.
van Boom, Synlett 1997, 11, 1263–1264.
b) V. Le Fouler, G. Duret, P. Bisseret, N. Blanchard,
Tetrahedron Lett. 2018, 59, 3349–3352; c) T. Y. Lam, Y.-
P. Wang, R. L. Danheiser, J. Org. Chem. 2013, 78, 9396–
9414; d) R. Pan, C. Shi, D. Zhang, Y. Tian, S. Guo, H.
Yao, A. Lin, Org. Lett. 2019, 21, 8915–8920; e) X. Y.
Chen, L. Wang, M. Frings, C. Bolm, Org. Lett. 2014, 16,
3796–3799; f) H. Kinoshita, A. Ueda, H. Fukumoto, K.
Miura, Org. Lett. 2017, 19, 882–885.
[9] Selected articles: a) D. Alvarez Dorta, A. Sivignon, T.
Chalopin, T. I. Dumych, G. Roos, R. O. Bilyy, D.
Deniaud, E.-M. Krammer, J. de Ruyck, M. F. Lensink, J.
Bouckaert, N. Barnich, S. G. Gouin, ChemBioChem
2016, 17, 936–952; b) C. Leteux, A. Veyrieres, J. Chem.
Soc. Perkin Trans. 1 1994, 2647–2655; c) D. Zhai, W. [20] J. Wang, C. Deng, Q. Zhang, Y. Chai, Org. Lett. 2019,
Zhai, R. M. Williams, J. Am. Chem. Soc. 1988, 110, 21, 1103–1107.
2501–2505; d) M. Lo Conte, A. Marra, A. Chambery, [21] O. Verho, M. P. Lati, M. Oschmann, J. Org. Chem. 2018,
S. S. Gurcha, G. S. Besra, A. Dondoni, J. Org. Chem.
2010, 75, 6326–6336.
83, 4464–4476.
Adv. Synth. Catal. 2021, 363, 1–12
11
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

RESEARCH ARTICLE
Directed Nickel-Catalyzed pseudo-Anomeric CÀ H Alkynyla-
tion of Glycals as an Approach towards C-Glycoconjugate
Synthesis
Adv. Synth. Catal. 2021, 363, 1–12
M. de Robichon, D. Branquet, J. Uziel, N. Lubin-Germain,
A. Ferry*