A general approach to C-Acyl glycosides via palladium/copper Co-catalyzed coupling reaction of glycosyl carbothioates and arylboronic acids

Article abstract of DOI:10.1016/j.tet.2021.131955

A general and efficient approach to the synthesis of various C-acyl glycosides has been developed via Pd₂(dba)₃/CuTC co-catalyzed cross-coupling reaction of glycosyl carbothioates with arylboronic acids. The reaction showed a broad s

Full text of DOI:10.1016/j.tet.2021.131955

Tetrahedron 82 (2021) 131955
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Tetrahedron
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A general approach to C-Acyl glycosides via palladium/copper Co-
catalyzed coupling reaction of glycosyl carbothioates and arylboronic
acids
Li-Na Wang 1, You-Hong Niu 1, Qing-Hui Cai, Qin Li**, Xin-Shan Ye*
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No. 38, Beijing, 100191, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A general and efficient approach to the synthesis of various C-acyl glycosides has been developed via
Pd2(dba)3/CuTC co-catalyzed cross-coupling reaction of glycosyl carbothioates with arylboronic acids.
The reaction showed a broad substrate scope and 25 examples were exhibited in 61%e97% isolated
yields. Furthermore, this reaction was applied to the gram-scale preparation of C-acyl glycosides. The
coupled products can be further transformed into diverse biologically useful compounds, as exemplified
by the synthesis of protected sergliflozin-A mimics.
Received 8 December 2020
Received in revised form
12 January 2021
Accepted 13 January 2021
Available online 21 January 2021
© 2021 Elsevier Ltd. All rights reserved.
Keywords:
C-Acyl glycoside
Glycosyl carbothioate
Arylboronic acid
Liebeskindesrogl cross-coupling reaction
1. Introduction
can be used as key intermediates in the preparation of relevant
C(sp3)-glycosidic linkages by using reduction or deoxyfluorination
Phenolic glycosides are widespread in nature, displaying various
activities including as potential anti-inflammatory agent (Fig. 1,
compound I) [1], antibacterial agent (compound II) [2], anticancer
agent (compound III) [3], antidiabetic agent (compound IV) [4],
allergy-preventive agent (compound V) [5] and so on. However, the
inherent instability of the glycosidic bond in these compounds
usually limits their diagnostic and therapeutic applications. C-
Glycosides, in which the oxygen atom of glycosidic linkage is
replaced by the carbon atom, are a class of compounds which can
be acted as surrogates of O-glycosides. This type of compounds also
exist in natural products and serve as key pharmacophores. Given
their in vivo resistance toward chemical and enzymatic hydrolysis,
C-glycosides have been proven to be more stable mimics of O-
glycosides [6].
methods to afford CH2- or CF2-linked glycosides. Consequently,
various methods have been developed to introduce acyl groups into
the anomeric carbon in glycosides. The most common methods for
the preparation of C-acyl glycosides are listed in Scheme 1. The first
approach involves additions of a C1-metalated glycosyl nucleophile
either to an aldehyde followed by an oxidation step [9], or to an
electrophilic acylating reagent [10] (Scheme 1a). Another strategy is
based on the addition of a nucleophile to C-glycosyl aldehyde
[11,12] followed by the oxidation of the corresponding alcohol
(Scheme 1b). In most cases, the success of this method mainly relies
on the synthesis of 1-formyl-C-glycosides: the formation of by-
products or presence of an anomeric mixture lowered the overall
yield and limited their use. Gong et al. described the synthesis of C-
acyl glycosides by the Ni-catalyzed coupling reaction between
glycosyl bromides and carboxylic acids or anhydrides (Scheme 1c).
This method is the direct synthesis of C-acyl glycosides; however,
C-Acyl glycosides, one type of C-glycosides, have shown
important biological activities such as inhibition against reactive
oxygen species, playing a major role in oxidative stress [7], and
glutamate-induced cell death [8]. Furthermore, C-acyl glycosides
with the exception of the mannose series, mixtures of
a/b-C-
glycosyl ketones were obtained [13]. These approaches require an
excess of heavy metals or strongly oxidizing conditions to unmask
the desired products. Indirect synthesis through other in-
termediates such as glycosyl nitriles [14] and benzothiazoles [15]
and dithianes [16] has been also reported, but it requires extra steps
or suffers from low stereoselectivity. Nicolas et al. described an
* Corresponding author.
** Corresponding author.
E-mail addresses: liqin@bjmu.edu.cn (Q. Li), xinshan@bjmu.edu.cn (X.-S. Ye).
These authors contributed equally to this work.
1
https://doi.org/10.1016/j.tet.2021.131955
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

L.-N. Wang, Y.-H. Niu, Q.-H. Cai et al.
Tetrahedron 82 (2021) 131955
indirect access to different acyl
b-C-glycosides from the reaction of
glyconitriles with organometallic reagents in moderate to good
yields (Scheme 1d) [14]. Although 1,2-trans-products were ob-
tained exclusively via neighboring group participation, this method
was plagued by the formation of glycals. In 2005, Dondoni et al.
took advantage of an indirect strategy to report the synthesis of
C-glycosyl ketones from -C-glycosyl benzothiazoles (Scheme 1e)
[15]. Schützenmeister et al. reported a one-pot, -selective method
for the synthesis of C-acyl glycosides, in which a CoreyeSeebach
umpolung reaction as the key step enables the -selective con-
b-
b
b
b
struction of the anomeric CeC bond starting from unprotected
carbohydrates and dithianes.
(Scheme 1f) [16]. In 2012, Liu et al. reported a b-selective C-
glycosylation [17]. This is the first N-heterocyclic carbene (NHC)
catalyzed acyl anion addition to the anomeric carbon of 2-
nitroglycals leading to the corresponding C-acyl glycosides
(Scheme 1g). However, the substrate scope of this Stetter-type re-
action was only limited to 2-formylpyridine and quinolone de-
rivatives. Therefore, the development of a general and mild method
to stereospecific C-acyl glycosides is still highly needed.
Fig. 1. Structures of some bioactive products.
In 2000, Liebeskind and Srogl reported a copper mediated,
palladium catalyzed CeC cross-coupling protocol of thioesters (TEs)
with boronic acids for the formation of simple ketones under aer-
obic conditions [18]. However, this reaction has not been applied to
highly functionalized molecules such as carbohydrates to synthe-
size more complex compounds [19]. As a continuation of our pre-
vious work on the synthesis of C-glycosides [20], we herein report a
mild and general approach to the synthesis of C-acyl glycosides
based on the Pd(0)/Cu(I) co-catalyzed cross coupling reaction be-
tween glycosyl carbothioates and arylboronic acids.
2. Results and discussion
At the outset of the project, we first examined the reactivity of D-
galactose-derived thioester 1a, which could be easily prepared
from HOBt/EDC$HCl promoted condensation of commercially
available methyl 2,3,4-tri-O-benzyl-a-D-galactopyranoside 6-
carboxylic acid (1a-1) [21] with p-toluene thiol in dichloro-
methane (CH2Cl2, DCM) (Scheme 2). A mixture of thioester 1a and
4-methoxyphenylboronic acid was treated with Pd2(dba)3 (2.5 mol
%), TFP (20.0 mol%) and CuTC (1.6 equiv.) in THF at 50 ꢀC, the desired
product 2 was produced in 39% yield (Table 1, entry 1). The
replacement of TFP by P(OEt)3 increased the yield significantly
(60%), which is consistent with the observation by Mihovilovic and
co-workers [22] (Table 1, entry 2). Increasing the amount of
Pd2(dba)3 from 2.5 mol% to 5.0 mol% and that of P(OEt)3 from
20.0 mol% to 40.0 mol% resulted in a decrease of the yield (Table 1,
entry 3). To further improve the yield, different temperatures were
explored (Table 1, entries 2, 4e6). When the reaction was carried
out at 50 ꢀC, 70 ꢀC or 120 ꢀC, the yield was not changed obviously.
Various solvents were also screened (Table 1, entries 2, 7e15), and
we found that solvent had a great influence on the reaction effi-
ciency. This reaction did not proceed in Et2O. Using DCM, toluene,
Scheme 1. General methods to prepare C-acyl glycosides.
Scheme 2. Preparation of thioester 1a.
2

L.-N. Wang, Y.-H. Niu, Q.-H. Cai et al.
Tetrahedron 82 (2021) 131955
Table 1
Optimization of the reaction Conditionsa.
entry ligand
Cu (I)
CuTC
base
solvent
temperature (oC) yieldb (%)
1
TFP
THF
THF
THF
THF
THF
THF
50
50
50
30
70
120
50
50
50
50
50
50
39
60
50
35
61
65
20
65
2
P(OEt)3 CuTC
P(OEt)3 CuTC
P(OEt)3 CuTC
P(OEt)3 CuTC
P(OEt)3 CuTC
P(OEt)3 CuTC
P(OEt)3 CuTC
P(OEt)3 CuTC
P(OEt)3 CuTC
P(OEt)3 CuTC
P(OEt)3 CuTC
P(OEt)3 CuTC
P(OEt)3 CuTC
P(OEt)3 CuTC
P(OEt)3 CuTC
P(OEt)3 CuCl
P(OEt)3 CuBr
P(OEt)3 CuI
3c
4
5
6
7
8
DCM
Toluene
CH3CN
Heptane
DMF
DMA
1,4-Dioxane 50
Et2O
MTBE
9
15e20
20e25
65
10
11
12
13
14
15
16
17
18
19
20
63
10e15
NR
93
NR
30
10e15
33
10e15
50
50
50
50
50
50
50
Cs2CO3 MTBE
MTBE
MTBE
MTBE
MTBE
P(OEt)3 CuOAc
a
Reaction conditions: thioester 1a (1.0 equiv.), 4-methoxyphenylboronic acid
(2.0 equiv.), Pd2(dba)3 (2.5 mol%), P(OEt)3 (20.0 mol%), CuTC (1.6 equiv.), solvent
(2.0 mL), under argon atmosphere. TFP ¼ tris-2-furylphosphine, CuTC ¼ copper (I)
thiophene-2-carboxylate, MTBE ¼ methyl tert-butyl ether.
b
Isolated yield. cPd2(dba)3 (5.0 mol%) and P(OEt)3 (40.0 mol%) were used.
CH3CN, heptane, DMF, DMA, 1,4-dioxane as the solvents, the reac-
tion proceeded, but the reaction yields were not satisfactory.
Methyl tert-butyl ether (MTBE) emerged as the best solvent,
affording 2 in 93% isolated yield (Table 1, entry 15). It should be
noted that the addition of a base such as Cs2CO3 led to failure of the
reaction (Table 1, entry 16). Finally, different copper salts such as
CuCl, CuBr, CuI, and CuOAc were tried, but the yields decreased
dramatically (Table 1, entries 17e20). Therefore, the optimized re-
action conditions are as follows: Pd2(dba)3 and CuTC as the co-
catalyst, P(OEt)3 as the ligand, and MTBE as the solvent at 50 ꢀC
(Table 1, entry 15).
Due to the good applicability of thioester 1a, we believed that
other glycosyl carbothioates would also work well to furnish the
corresponding C-acyl glycosides. Therefore, we designed several
Scheme 3. Preparation of thioesters 1 b-1g.
thioesters derived from D-glucose, D-galactose, D-mannose, and L-
tetra-O-benzyl-b-D-glucopyranosyl carbothioate 1b with 4-
rhamnose (Scheme 3). These thioesters were prepared from
commercially available benzyl-protected glycopyranoses 1b-1,1c-1,
1d-1, 1f-1, followed by the sequential reactions including acetyla-
tion [23], cyanidation [24], hydrolysis of the cyano group and thi-
oesterification of the obtained acids. The acetates 1b-2, 1c-2, 1d-2,
1f-2 were treated with TMSCN in the presence of BF3$OEt2,
affording the corresponding glycosyl cyanides. The glycosyl cya-
nides were then hydrolyzed with 4 M HCl to furnish carboxylic
acids, which were directly applied to the next step without further
purification. The carboxylic acids were converted into thioesters by
treatment of the acids with p-toluene thiol under the promotion of
HOBt/EDC$HCl in dichloromethane to afford the corresponding
thioesters 1b-1g in satisfactory yields.
methoxyphenylboronic acid was chosen. To our delight, thioester
1b was well accommodated to furnish the corresponding C-acyl
glycoside 3 in 85% isolated yield. Having achieved the primary re-
sults, we further investigated the scope of this conversion by using
diversely substituted arylboronic acids as substrates. The results
were summarized in Scheme 4. In general, a multitude of arylbor-
onic acids containing electron-withdrawing or electron-donating
substituents on the benzene ring underwent efficient conversion
to furnish the corresponding acyl C-glycosides 4e11 in yields
ranging from 61% to 97%. In addition, the position of substituents on
benzene ring and the type of substituents such as phenyl, CH3,
OCH3, OBn, COOCH2CH3, NO2, and CF3 groups almost did not in-
fluence the outcome of this transformation, and the desired prod-
ucts were obtained in high yields. It should be mentioned that the
vinylboronic acid was compatible with the reaction conditions and
With these thioesters in hand, we started to examine the sub-
strate scope of the reaction. The cross-coupling reaction of 2,3,4,6-
3

L.-N. Wang, Y.-H. Niu, Q.-H. Cai et al.
Tetrahedron 82 (2021) 131955
Scheme 4. The scope of arylboronic acid substrates.
the reaction proceeded smoothly. The substrates containing het-
eroaromatic groups could increase the number of coordination sites
with palladium, which would hinder the catalytic efficiency and
hence bring about a challenge to regioselective functionalization.
To our surprise, furylboronic acid exhibited good compatibility with
our method, the product 13 was obtained in 70% yield.
Next, we turn our attention to probing the feasibility of other
thioesters from D-galactose, L-rhamnose and D-mannose. As shown
in Scheme 5, the coupling of benzyl-protected thioesters 1c, 1e and
1f with 4-methoxyphenylboronic acid under the optimal condi-
tions afforded products 18, 21 and 24 in 84%, 85%, and 93% yields
respectively, which are comparable to the reaction yield of 1b with
4-methoxyphenylboronic acid. The reaction of thioesters 1c, 1d, 1e,
1f and 1g with different arylboronic acids also provided the cor-
responding products in satisfactory yields. It is worthy to note that
both 1,2-cis and 1,2-trans anomers of the carbothioates can be
smoothly converted into the corresponding C-acyl glycosides with
the retention of anomeric configuration.
Scheme 5. The scope of glycosyl carbothioate substrates.
Sergliflozin-A, an aryl-b-D-glucopyranoside, is a highly selective
and potent inhibitor of human low-affinity sodium glucose
cotransporter 2 (SGLT2) [25]. However, the metabolic instability
restricted its development into a drug. Currently, researches on
SGLT2 inhibitors mainly focused on the modifications of the agly-
cone unit of sergliflozin [26]. Therefore, taking the C-acyl glycoside
11 as a key intermediate, we synthesized several benzyl-protected
sergliflozin-A analogues via facile transformations (Scheme 6).
The CF2 group has been considered as the isostere of oxygen in
biologically active compounds [27], which can increase the stability
of these molecules and improve their pharmacokinetic properties
[12]. Thus, we converted the ketone into the difluorinated deriva-
tive 28 by treating compound 11 with diethylaminosulfurtri-
fluoride (DAST) at 80 ꢀC [11a]. The carbonyl group in 11 was also
reduced by NaBH4, affording alcohol 29 in 95% yield [10]. Besides,
treatment of 11 with NH2OH$HCl, KHCO3, and DIPEA in MeOH at
Scheme 6. Further product modifications as analogues of sergliflozin-A.a.
between glycosyl carbothioates and arylboronic acids. The
approach allows a wide range of substrates and functionalities to be
used. As exemplified by the preparation of C-acyl glycoside 11, the
reaction could be scaled up. Using compound 11 as a key inter-
mediate, we successfully synthesized sergliflozin A mimics 28, 29
and 30, which could be used as the precursors of potential SGLT2
inhibitors. The disclosed protocol may find wide applications in the
70 ꢀC furnished
a, b-unsaturated ketone 30 in 92% yield.
In conclusion, we have developed a mild and efficient method
for the stereospecific preparation of C-acyl glycosides in 61%e97%
yield via Pd2(dba)3/CuTC co-catalyzed cross-coupling reaction
4

L.-N. Wang, Y.-H. Niu, Q.-H. Cai et al.
Tetrahedron 82 (2021) 131955
preparation of many biologically important C-glycosides.
128.4, 128.10, 128.07, 127.8, 127.6, 127.5, 127.5, 123.4, 99.4, 78.3, 76.4,
76.1, 75.6, 73.9, 73.2, 56.1, 21.4. HRMS (ESI) m/z calcd for
3. Experimental section
C
35H40NO6S [M þ NH4]þ 602.2576; found: 602.2585.
2,3,4,6-Tetra-O-benzyl-a/b-D-glucopyranosyl cyanide (1b-3).
3.1. General information
An oven-dried flask fitted with a magnetic stirring-bar was charged
with the activated 4 Å molecular sieves (2.00 g), a solution of 1b-2
(5.00 g, 8.58 mmol) in anhydrous CH2Cl2 (20.0 mL) was added
under an argon atmosphere. After the solution being cooled to 0 ꢀC,
TMSCN (2.20 mL, 17.16 mmol) and BF3$OEt2 (2.20 mL, 17.16 mmol)
were added dropwise. The mixture was stirred at room tempera-
ture for 12 h. Then the reaction was quenched with saturated
NaHCO3, the solid was filtered off and the filtrate was concentrated.
The residue was purified by column chromatography on silica gel
(petroleum ether: ethyl acetate ¼ 4: 1, v/v) to afford 1b-3 as
All reagents and solvents were dried commonly before use ac-
cording to standard procedures. Commercially available reagents
were used without further purification unless otherwise noted.
CH2Cl2 was distilled over CaH2. Reactions were monitored by
analytical thin-layer chromatography (TLC) on silica gel-coated
aluminium plates (60 F254). Spots were detected under UV light
(254 nm) and charring with a solution of (NH4)6Mo7O24$4H2O
(24.00 g, 19.4 mmol) and Ce(NH4)2(NO3)6 (0.50 g, 0.90 mmol) in
sulfuric acid (5%, 500 mL). Column chromatography was performed
on silica gel (200e300 mesh). 1H NMR spectra were recorded at
colorless oil (
a:
b
¼ 1:1.1, 3.50 g, 65%). 1H NMR (400 MHz, CDCl3)
d
7.33e7.12 (m, 42H), 4.96e4.42 (m, 16.8H, PhCH2), 4.61 (d,
room temperature in CDCl3 with TMS (
standard. 13C NMR spectra were obtained by using the same NMR
spectrometer and were calibrated with CDCl3 (
¼ 77.00 ppm). The
d
¼ 0 ppm) as internal
J ¼ 5.9 Hz,1H,
t, J ¼ 9.3 Hz, 1H,
8.4H, -H-2,
-H-3), 3.44e3.37 (m, 1.1H, b
a
-H-1), 4.04 (d, J ¼ 10.0 Hz,1.1H,
-H-3), 3.85e3.79 (m, 1H,
-H-4, -H-6,
-H-60), 3.58 (pseudo t,
-H-5). The spectroscopic
b
-H-1), 3.89 (pseudo
a
a-H-5), 3.78e3.6 (m,
d
a
,
b
a,
b
a
,
b
a, b
following standard abbreviations are used to indicate multiplicity:
s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet,
dd ¼ doublet of doublets, dt ¼ doublet of triplets, and br ¼ broad.
High resolution mass spectra were obtained using a Waters Xevo
G2 Q-TOF mass spectrometer, and nominal and exact m/z values
were reported in daltons. Optical rotations were measured on a
Hanon P850 Automatic Polarimeter.
J ¼ 8.8 Hz, 1H,
b
data coincide with the previous report [24].
S-(p-Tolyl) (2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzy-
loxy)methyl)tetrahydro-2H-pyran-2-carbothioate (1b). To the
ice-cooled solution of compound 1b-3 (0.50 g, 0.91 mmol) in 1,4-
dioxane: H2O ¼ 10 : 1 (5.50 mL), 4 M HCl in 1,4-dioxane (6.0 mL)
was added. The mixture was stirred at 60 ꢀC for 12 h under argon
atmosphere until TLC indicated the reaction was complete. Then
the mixture was concentrated in vacuum and the crude product
was applied to the next step reaction without further purification.
The crude product was dissolved in CH2Cl2 (10.0 mL), then HOBt
(0.14 g, 1.00 mmol), EDC$HCl (0.19 g, 1.00 mmol) and p-toluenethiol
(0.14 g, 1.10 mmol) were added. The mixture was stirred overnight
at room temperature. The reaction mixture was diluted with
saturated aqueous NaHCO3 and the mixture was extracted with
CH2Cl2 for three times. The combined organic phase was washed
with brine, dried over anhydrous Na2SO4 and concentrated in
vacuum. The residue was purified by column chromatography on
silica gel (petroleum ether: ethyl acetate ¼ 20 : 1, v/v), and further
purification was performed (toluene: CH3CN ¼ 40 : 1, v/v) to afford
3.2. Preparation of glycosyl carbothioates
(2S,3R,4S,5R,6S)-3,4,5-Tris(benzyloxy)-6-methoxytetrahydro-
2H-pyran-2-carboxylic acid (1a-1). To a solution of methyl 2,3,4-
tri-O-benzyl-a-D-galactopyranoside (0.10 g, 0.22 mmol) in CH2Cl2:
H2O ¼ 2 : 1 (6.0 mL), BAIB (0.17 g, 0.52 mmol) and TEMPO (7.0 mg,
0.04 mmol) were added and the mixture was stirred overnight at
room temperature. The reaction mixture was quenched with
Na2S2O3 and then extracted with CH2Cl2 for three times. The
organic phase was combined and washed with brine, dried over
anhydrous Na2SO4 and concentrated in vacuum. The crude product
was purified by column chromatography on silica gel (CH2Cl2:
MeOH ¼ 20 : 1, v/v) to afford 1a-1 as colorless oil (99.0 mg, 96%). 1H
1b as a white solid (0.24 g, 30%). [
NMR (600 MHz, CDCl3)
a
]25D ¼ þ28.0 (c ¼ 1.0, CHCl3); 1H
NMR (400 MHz, DMSO‑d6)
d
7.41e7.23 (m, 15H), 4.88 (d, J ¼ 3.5 Hz,
d
7.40e7.17 (m, 24H), 4.89 (d, J ¼ 11.1 Hz,
1H), 4.84 (d, J ¼ 11.1 Hz, 1H), 4.80 (d, J ¼ 12.1 Hz, 1H), 4.73 (d,
J ¼ 12.2 Hz, 1H), 4.69 (d, J ¼ 12.0 Hz, 1H), 4.65 (d, J ¼ 12.0 Hz, 1H),
4.53 (d, J ¼ 11.1 Hz, 1H), 4.41 (dd, J ¼ 3.1, 1.7 Hz, 1H), 4.26 (d,
J ¼ 1.5 Hz, 1H), 3.94 (dd, J ¼ 10.2, 3.0 Hz, 1H), 3.81 (dd, J ¼ 10.2,
3.5 Hz, 1H), 3.29 (s, 3H). The spectroscopic data coincide with the
previous report [21].
1H), 4.85 (d, J ¼ 11.1 Hz, 1H), 4.82 (d, J ¼ 10.8 Hz, 1H), 4.72e4.69 (m,
2H), 4.66e4.62 (m, 2H), 4.61 (d, J ¼ 10.8 Hz, 1H), 4.07 (d, J ¼ 9.4 Hz,
1H), 3.85 (t, J ¼ 9.0 Hz, 1H), 3.80e3.68 (m, 4H), 3.57e3.55 (m, 1H),
2.38 (s, 3H); 13C NMR (151 MHz, CDCl3)
d 195.5, 139.9, 138.4, 138.2,
137.9, 137.6, 134.6, 130.2, 128.43, 128.38, 128.3, 128.0, 127.85, 127.82,
127.77, 127.7, 127.6, 123.3, 86.11, 83.2, 80.3, 79.5, 77.6, 75.6, 75.2,
75.1, 73.5, 68.6, 21.4. HRMS (ESI) m/z calcd for C42H46NO6S
[M þ NH4]þ 692.3046; found: 692.3063.
S-(p-Tolyl)
(2S,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-
methoxytetrahydro-2H-pyran-2-carbothioate (1a). To an ice-
cooled solution of compound 1a-1 (100.0 mg, 0.21 mmol) in
CH2Cl2 (5.0 mL), HOBt (32.0 mg, 0.24 mmol), EDC$HCl (45.0 mg,
0.23 mmol) were added. After 30 min, p-toluenethiol (32.0 mg,
0.26 mmol) was added, and the mixture was stirred at room tem-
perature overnight. The reaction was quenched with saturated
NaHCO3 and the mixture was extracted with CH2Cl2 for three times,
and the combined organic phase was washed with brine, dried over
anhydrous Na2SO4 and concentrated in vacuum. The crude product
was purified by flash column chromatography on silica gel (pe-
troleum ether: ethyl acetate ¼ 25 : 1, v/v) to afford 1a as a white
2,3,4,6-Tetra-O-benzyl-b-D-galactopyranosyl cyanide (1c-3).
The same procedure for the synthesis of 1b-3 was applied, yielding
1c-3 (1.20 g, 40%) as a white solid. [
]25D ¼ þ21.3 (c ¼ 5.4, CHCl3);
1H NMR (400 MHz, CDCl3)
7.38e7.22 (m, 20H), 4.93 (d, J ¼ 11.4 Hz,
a
d
1H), 4.89 (pseudo s, 2H), 4.73 (d, J ¼ 11.7 Hz,1H), 4.70 (d, J ¼ 11.8 Hz,
1H), 4.57 (d, J ¼ 11.5 Hz, 1H), 4.46 (d, J ¼ 11.8 Hz, 1H), 4.40 (d,
J ¼ 11.8 Hz, 1H), 4.17 (t, J ¼ 9.7 Hz, 1H), 4.00 (d, J ¼ 10.0 Hz, 1H), 3.93
(d, J ¼ 2.7 Hz, 1H), 3.60e3.47 (m, 4H); 13C NMR (101 MHz, CDCl3)
d
138.2, 137.8, 137.6, 137.3, 128.6, 128.49, 128.47, 128.4, 128.13,
128.07, 128.0,127.94,127.93,127.8,127.6,116.9, 83.0, 78.3, 76.3, 76.0,
solid (76.0 mg, 62%). [
a
]25D ¼ ꢁ32.3 (c ¼ 6.7, CHCl3); 1H NMR
74.9, 73.7, 73.5, 72.8, 68.4, 68.0. HRMS (ESI) m/z calcd for
C
35H39N2O5 [M þ NH4]þ 567.2859, found: 567.2858.
(400 MHz, CDCl3)
d
7.38e7.18 (m, 19H), 4.92e4.85 (m, 3H), 4.82 (d,
J ¼ 11.8 Hz, 1H), 4.72 (d, J ¼ 11.8 Hz, 1H), 4.69 (d, J ¼ 12.1 Hz, 1H),
4.53 (d, J ¼ 11.1 Hz, 1H), 4.41e4.36 (m, 2H), 4.14 (dd, J ¼ 10.0, 3.6 Hz,
1H), 3.95 (dd, J ¼ 10.0, 2.9 Hz,1H), 3.47 (s, 3H), 2.38 (s, 3H); 13C NMR
S-(p-Tolyl) (2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzy-
loxy)methyl)tetrahydro-2H-pyran-2-carbothioate (1c). Com-
pound 1c was prepared from 1c-3 according to the same procedure
(101 MHz, CDCl3)
d 198.2, 139.7, 138.5, 138.41, 138.39, 134.7, 130.0,
5

L.-N. Wang, Y.-H. Niu, Q.-H. Cai et al.
Tetrahedron 82 (2021) 131955
for the synthesis of 1b (yield: 1.05 g, 35%, as a white solid).
[
d
a
]25D ¼ þ28.0 (c ¼ 1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
[
a
]25D ¼ þ20.0 (c ¼ 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
7.36e7.25 (m, 22H), 7.20 (d, J ¼ 8.0 Hz, 2H), 4.99 (d, J ¼ 11.8 Hz,
7.48e7.46 (m, 2H), 7.37e7.27 (m, 13H), 4.99 (d, J ¼ 11.4 Hz, 1H),
d
4.94e4.90 (m, 2H), 4.66 (pseudo d, J ¼ 10.2 Hz, 3H), 4.20 (d,
J ¼ 1.3 Hz, 1H), 4.02 (dd, J ¼ 3.0, 1.3 Hz, 1H), 3.63 (t, J ¼ 9.3 Hz, 1H),
3.50 (dd, J ¼ 9.3, 2.9 Hz, 1H), 3.36e3.30 (m, 1H), 1.35 (d, J ¼ 6.1 Hz,
1H), 4.78 (d, J ¼ 10.3 Hz, 1H), 4.74 (d, J ¼ 11.8 Hz, 1H), 4.70 (d,
J ¼ 11.8 Hz, 1H), 4.68e4.62 (m, 2H), 4.51 (d, J ¼ 11.9 Hz, 1H), 4.45 (d,
J ¼ 11.9 Hz, 1H), 4.23 (t, J ¼ 9.4 Hz, 1H), 4.01 (d, J ¼ 9.5 Hz, 1H), 3.98
(d, J ¼ 2.8 Hz, 1H), 3.69e3.61 (m, 4H), 2.37 (s, 3H); 13C NMR
1H); 13C NMR (101 MHz, CDCl3)
d 138.1, 137.8, 137.0, 128.6, 128.5,
128.4, 128.2, 128.0, 127.9, 127.85, 127.78, 115.6, 79.9, 79.3, 75.4, 75.0,
73.8, 72.83, 72.80, 65.3, 17.8. HRMS (ESI) m/z calcd for C28H33N2O4
[M þ NH4]þ 461.2440; found: 461.2440. For 1f-4: a white solid.
(101 MHz, CDCl3)
d 195.3, 139.67, 138.71, 138.2, 138.1, 137.8, 134.6,
130.1, 128.4, 128.33, 128.29, 128.2, 127.9, 127.8, 127.70, 127.68,
127.53, 127.48, 123.6, 83.9, 83.7, 77.8, 76.8, 75.5, 74.4, 73.60, 73.55,
72.7, 68.70 21.4. HRMS (ESI) m/z calcd for C42H46NO6S [M þ NH4]þ
692.3046; found: 692.3058.
[
d
a
]25D ¼ ꢁ24.0 (c ¼ 1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
7.34e7.31 (m, 15H), 4.98 (d, J ¼ 10.9 Hz, 1H), 4.71e4.63 (m, 5H),
4.59 (d, J ¼ 11.6 Hz, 1H), 3.89e3.85 (m, 2H), 3.81e3.74 (m, 1H), 3.66
2,3,4,6-Tetra-O-benzyl-
and 2,3,4,6-tetra-O-benzyl-
b
-
D
-mannopyranosyl cyanide (1d-3)
-mannopyranosyl cyanide (1d-4).
(t, J ¼ 9.0 Hz, 1H), 1.42 (d, J ¼ 6.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
a
-
D
d 138.2, 137.8, 137.1, 128.65, 128.56, 128.4, 128.2, 128.04, 127.97,
The same procedure for the synthesis of 1b-3 was applied, yielding
1d-3 (0.45 g, 27%) and 1d-4 (0.53 g, 49%). For 1d-3: a white solid.
127.9, 127.8, 115.6, 79.9, 79.3, 75.5, 75.0, 73.8, 73.0, 72.8, 65.4, 17.9.
HRMS (ESI) m/z calcd for C28H33N2O4 [M þ NH4]þ 461.2440; found:
461.2440.
[
a
]25D ¼ ꢁ7.8 (c ¼ 2.7, CHCl3). 1H NMR (400 MHz, CDCl3)
d
7.47e7.45 (m, 2H), 7.36e7.24 (m, 16H), 7.17e7.15 (m, 2H), 4.98 (d,
S-(p-Tolyl)
(2S,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-6-
J ¼ 11.4 Hz, 1H), 4.92 (d, J ¼ 11.4 Hz, 1H), 4.84 (d, J ¼ 10.8 Hz, 1H),
4.65e4.53 (m, 5H), 4.21 (d, J ¼ 1.3 Hz, 1H), 4.02 (dd, J ¼ 3.0, 1.3 Hz,
1H), 3.92 (t, J ¼ 9.4 Hz, 1H), 3.74e3.68 (m, 2H), 3.54 (dd, J ¼ 9.2,
methyltetrahydro-2H-pyran-2-carbothioate (1f). Compound 1f
was prepared from 1f-3 according to the same procedure for the
synthesis of 1b (yield: 0.60 g, 30%, as a white solid). [
a
]25D ¼ ꢁ33.0
2.9 Hz, 1H), 3.46e3.42 (m, 1H); 13C NMR (101 MHz, CDCl3)
d
138.0,
(c ¼ 1.0, CHCl3). 1H NMR (600 MHz, CDCl3)
d 7.35e7.22 (m, 19H),
137.8, 137.6, 137.4, 128.6, 128.42, 128.37, 128.1, 128.00, 127.97, 127.95,
127.9, 127.6, 116.0, 82.4, 80.6, 75.4, 74.7, 74.2, 74.0, 73.6, 72.7, 68.9,
67.5. HRMS (ESI) m/z calcd for C35H39N2O5 [M þ NH4]þ 567.2859;
4.96 (d, J ¼ 10.8 Hz, 1H), 4.87 (d, J ¼ 11.4 Hz, 1H), 4.72e4.60 (m, 4H),
4.38 (dd, J ¼ 2.9, 1.4 Hz, 1H), 4.07 (d, J ¼ 1.4 Hz, 1H), 3.74 (t,
J ¼ 9.3 Hz, 1H), 3.60 (dd, J ¼ 9.4, 2.8 Hz, 1H), 3.50e3.46 (m, 1H), 2.38
found: 567.2854. For 1d-4: a white solid. [
a
]25D ¼ þ31.3 (c ¼ 6.1,
(s, 3H), 1.48 (d, J ¼ 6.1 Hz, 3H); 13C NMR (151 MHz, CDCl3)
d 198.7,
CHCl3). 1H NMR (400 MHz, CDCl3)
d
7.36e7.16 (m, 20H), 4.85 (d,
139.7, 138.4, 138.3, 138.0, 134.7, 130.1, 128.44, 128.40, 128.13, 128.11,
128.08, 127.8, 127.7, 127.6, 127.5, 123.6, 83.6, 83.2, 79.8, 76.5, 76.0,
75.6, 75.2, 72.1, 21.4, 18.1. HRMS (ESI) m/z calcd for C35H40NO5S
[M þ NH4]þ 586.2627; found: 586.2623.
J ¼ 10.9 Hz, 1H), 4.78 (d, J ¼ 2.6 Hz, 1H), 4.68e4.49 (m, 7H), 4.01 (t,
J ¼ 9.1 Hz, 1H), 3.92 (dd, J ¼ 9.1, 3.0 Hz, 1H), 3.87e3.77 (m, 3H), 3.71
(dd, J ¼ 11.0, 2.0 Hz, 1H); 13C NMR (101 MHz, CDCl3)
d 138.0, 137.9,
137.7, 137.0, 128.6, 128.5, 128.45, 128.38, 128.37, 128.2, 128.0, 127.90,
127.87, 127.84, 127.75, 127.7, 115.4, 79.8, 77.1, 75.2, 74.8, 73.8, 73.4,
72.8, 72.7, 68.4, 65.3. HRMS (ESI) m/z calcd for C35H39N2O5
[M þ NH4]þ 567.2859; found: 567.2865.
S-(p-Tolyl)
(2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-6-
methyltetrahydro-2H-pyran-2-carbothioate (1g). Compound 1g
was prepared from 1f-4 according to the same procedure for the
synthesis of 1b (yield: 0.50 g, 33%, as a white solid). [
a
]25D ¼ þ22.7
S-(p-Tolyl) (2R,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzy-
loxy)methyl)tetrahydro-2H-pyran-2-carbothioate (1d). Com-
pound 1d was prepared from 1d-3 according to the same procedure
for the synthesis of 1b (yield: 0.45 g, 31%, as a white solid).
(c ¼ 1.7, CHCl3). 1H NMR (400 MHz, CDCl3)
d 7.38e7.22 (m, 19H),
4.93 (d, J ¼ 10.7 Hz, 1H), 4.69 (pseudo s, 2H), 4.64e4.61 (m, 2H),
4.55 (d, J ¼ 11.7 Hz, 1H), 4.50 (d, J ¼ 11.8 Hz, 1H), 4.38 (t, J ¼ 2.7 Hz,
1H), 3.91e3.84 (m, 1H), 3.67 (t, J ¼ 9.2 Hz, 1H), 3.53 (dd, J ¼ 9.2,
3.0 Hz, 1H), 2.37 (s, 3H), 1.44 (d, J ¼ 6.1 Hz, 3H); 13C NMR (101 MHz,
[
d
a
]25D ¼ þ21.3 (c ¼ 5.4, CHCl3). 1H NMR (400 MHz, CDCl3)
7.42e7.21 (m, 24H), 4.92 (pseudo t, J ¼ 10.6 Hz, 2H), 4.84 (d,
CDCl3) d 199.3, 139.9, 138.3, 138.2, 137.8, 134.7, 130.1, 128.42, 128.41,
J ¼ 12.1 Hz, 1H), 4.73e4.70 (m, 2H), 4.67e4.60 (m, 3H), 4.41 (dd,
J ¼ 2.9, 1.4 Hz, 1H), 4.14 (d, J ¼ 1.4 Hz, 1H), 4.05 (t, J ¼ 9.6 Hz, 1H),
3.91e3.84 (m, 2H), 3.68 (dd, J ¼ 9.4, 2.8 Hz, 1H), 3.63e3.59 (m, 1H),
128.3, 128.1, 128.0, 127.8, 127.74, 127.70, 127.6, 123.0, 81.6, 80.4, 79.1,
75.4, 73.8, 73.7, 72.6, 71.9, 21.3, 18.2. HRMS (ESI) m/z calcd for
C
35H40NO5S [M þ NH4]þ 586.2627; found: 586.2620.
2.41 (s, 3H); 13C NMR (101 MHz, CDCl3)
d 198.8, 139.7, 138.6, 138.5,
138.2, 138.0, 134.8, 130.1, 128.5, 128.4, 128.3, 128.12, 128.07, 127.9,
127.85, 127.76, 127.7, 127.6, 127.5, 123.7, 83.7, 83.1, 80.4, 75.9, 75.4,
75.1, 74.7, 73.8, 72.2, 69.3, 21.4. HRMS (ESI) m/z calcd for
3.3. General procedure for the cross-coupling reaction
An oven-dried flask fitted with a magnetic stirring-bar was
charged with glycosyl carbothioate (1.0 equiv.), aryl boronic acid
(2.0 equiv.) and tert-butyl methyl ether (2.0 mL) under an argon
atmosphere. Pd2(dba)3 (2.5 mol%), P(OEt)3 (20.0 mol%), and CuTC
(1.6 equiv.) were added, then the mixture was stirred at 50 ꢀC for
24 h. After completion, the reaction mixture was filtered through
Celite and the filtrate was concentrated in vacuum. The residue was
purified by column chromatography on silica gel (eluting with
petroleum ether/ethyl acetate) to give the desired product.
C
42H46NO6S [M þ NH4]þ 692.3046; found: 692.3048.
S-(p-Tolyl) (2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzy-
loxy)methyl)tetrahydro-2H-pyran-2-carbothioate (1e). Com-
pound 1e was prepared from 1d-4 according to the same procedure
for the synthesis of 1b (yield: 0.53 g, 34%, a white solid).
[
d
a
]25D ¼ þ12.0 (c ¼ 1.5, CHCl3). 1H NMR (400 MHz, CDCl3)
7.42e7.14 (m, 24H), 4.86 (d, J ¼ 10.6 Hz, 1H), 4.77e4.65 (m, 4H),
4.60 (d, J ¼ 12.1 Hz, 1H), 4.56e4.45 (m, 3H), 4.38 (t, J ¼ 2.8 Hz, 1H),
4.10e4.01 (m, 2H), 3.90e3.82 (m, 2H), 3.58 (dd, J ¼ 8.7, 3.0 Hz, 1H),
(4-Methoxyphenyl)((2S,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-
methoxytetrahydro-2H-pyran-2-yl)methanone (2). This com-
pound was synthesized from 1a (30.0 mg, 0.05 mmol) and 4-
methoxyphenylboronic acid (15.0 mg, 0.10 mmol) according to
the general procedure. The product 2 was obtained in 93% yield
2.37 (s, 3H); 13C NMR (101 MHz, CDCl3)
d 199.0, 139.9, 138.3, 138.2,
138.1, 137.8, 134.7, 130.1, 128.4, 128.33, 128.30, 128.05, 127.95, 127.8,
127.72, 127.68, 127.6, 127.5, 122.9, 81.4, 80.2, 75.1, 73.8, 73.7, 73.5,
72.4, 71.9, 69.2, 21.3. HRMS (ESI) m/z calcd for C42H42NaO6S [M þ
Na]þ 697.2600; found: 697.2609.
(27.0 mg) as colorless oil. [
(400 MHz, CDCl3) d 7.94e7.90 (m, 2H), 7.39e7.25 (m,10H), 7.15e7.12
a
]25D ¼ þ9.8 (c ¼ 7.8, CHCl3). 1H NMR
2,3,4-Tri-O-benzyl-
b-
D-rhamnopyranosyl cyanide (1f-3) and
2,3,4-tri-O-benzyl- -rhamnopyranosyl cyanide (1f-4). The
same procedure for the synthesis of 1b-3 was applied, yielding 1f-3
(0.50 g, 37%) and 1f-4 (0.60 g, 40%). For 1f-3: a white solid.
a
-
D
(m, 3H), 7.06e7.03 (m, 2H), 6.88e6.84 (m, 2H), 4.91e4.84 (m, 4H),
4.74e4.71 (m, 2H), 4.69 (d, J ¼ 9.4 Hz, 1H), 4.35 (d, J ¼ 11.3 Hz, 1H),
4.31 (dd, J ¼ 2.9, 1.5 Hz, 1H), 4.15 (dd, J ¼ 10.1, 3.5 Hz, 1H), 4.08 (dd,
6

L.-N. Wang, Y.-H. Niu, Q.-H. Cai et al.
Tetrahedron 82 (2021) 131955
J ¼ 10.1, 2.9 Hz, 1H), 3.84 (s, 3H), 3.41 (s, 3H); 13C NMR (101 MHz,
(pseudo s, 2H), 4.85 (d, J ¼ 10.9 Hz,1H), 4.74 (d, J ¼ 10.5 Hz,1H), 4.61
(d, J ¼ 10.1 Hz, 3H), 4.54 (d, J ¼ 12.0 Hz,1H), 4.49 (d, J ¼ 12.0 Hz,1H),
4.44 (d, J ¼ 7.1 Hz, 1H), 4.40 (d, J ¼ 7.1 Hz,1H), 4.03 (t, J ¼ 9.2 Hz,1H),
3.86 (t, J ¼ 8.3 Hz, 1H), 3.76 (d, J ¼ 9.8 Hz, 1H), 3.68 (d, J ¼ 5.5 Hz,
CDCl3) d 195.0, 163.5, 138.6, 138.5, 138.1, 131.6, 128.9, 128.39, 128.37,
128.05, 128.02, 127.9, 127.7, 127.57, 127.55, 127.3, 113.5, 99.4, 78.6,
77.5, 76.1, 75.3, 74.8, 73.7, 73.3, 56.2, 55.4. HRMS (ESI) m/z calcd for
C
35H37O7 [M þ H]þ 569.2539; found: 569.2542.
3H),1.43 (t, J ¼ 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 194.3,165.7,
(4-Methoxyphenyl)((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-
139.0, 138.5, 138.1, 138.0, 137.8, 134.5, 129.7, 129.2, 128.5, 128.4,
128.3, 128.0, 127.9, 127.70, 127.67, 127.6, 87.0, 80.2, 79.5, 79.3, 78.1,
75.7, 75.2, 75.02, 73.5, 69.1, 61.4, 14.3. HRMS (ESI) m/z calcd for
((benzyloxy)methyl) tetrahydro-2H-pyran-2-yl)methanone (3).
This compound was synthesized from thioester 1b (30.0 mg,
0.04 mmol) and 4-methoxyphenylboronic acid (14.0 mg,
0.08 mmol) according to the general procedure. The product 3 was
obtained in 85% yield (25.0 mg) as a white solid. 1H NMR (400 MHz,
C
44H48NO8 [M þ NH4]þ 718.3380; found: 718.3369.
(3-Nitrophenyl)((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-
((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methanone (8).
This compound was synthesized from thioester 1b (30.0 mg,
0.04 mmol) and 3-nitrophenylboronic acid (15.0 mg, 0.08 mmol)
according to the general procedure. The product 8 was obtained in
CDCl3)
d 8.07e8.05 (m, 2H), 7.40e7.23 (m, 13H), 7.24e7.14 (m, 5H),
7.02e7.00 (m, 2H), 6.91e6.87 (m, 2H), 4.95 (d, J ¼ 11.0 Hz, 1H), 4.91
(d, J ¼ 11.0 Hz, 1H), 4.85 (d, J ¼ 10.9 Hz, 1H), 4.69 (d, J ¼ 10.4 Hz, 1H),
4.62e4.49 (m, 4H), 4.51 (d, J ¼ 12.0 Hz, 1H), 4.03 (t, J ¼ 9.2 Hz, 1H),
3.89e3.82 (m, 4H), 3.78e3.65 (m, 4H). The spectroscopic data
coincide with the previous report [10].
97% yield (29.0 mg) as a white solid. [
a
]25D ¼ þ14.0 (c ¼ 1.6, CHCl3).
1H NMR (400 MHz, CDCl3)
d
8.83 (t, J ¼ 1.9 Hz, 1H), 8.38e8.32 (m,
2H), 7.54 (t, J ¼ 8.0 Hz, 1H), 7.36e7.26 (m, 13H), 7.21e7.14 (m, 5H),
7.07e7.02 (m, 2H), 4.94 (pseudo s, 2H), 4.86 (d, J ¼ 10.8 Hz,1H), 4.79
(d, J ¼ 10.7 Hz, 1H), 4.62e4.53 (m, 4H), 4.48 (d, J ¼ 12.1 Hz, 1H), 4.00
(t, J ¼ 9.2 Hz, 1H), 3.88 (t, J ¼ 8.6 Hz, 1H), 3.77e3.66 (m, 4H); 13C
o-Tolyl((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)
methyl)tetrahydro-2H-pyran-2-yl)methanone (4). This com-
pound was synthesized from thioester 1b (30.0 mg, 0.04 mmol) and
2-tolylboronic acid (12.0 mg, 0.08 mmol) according to the general
procedure. The product 4 was obtained in 88% yield (25.0 mg) as a
NMR (101 MHz, CDCl3)
d 192.7, 148.3, 138.2, 137.94, 137.85, 137.5,
136.8, 134.9, 129.6, 128.50, 128.47, 128.3, 128.2, 128.0, 127.94, 127.90,
127.8, 127.71, 127.70, 127.65, 127.5, 124.3, 86.9, 80.0, 79.8, 79.0, 77.9,
75.8, 75.2, 75.0, 73.4, 68.9. HRMS (ESI) m/z calcd for C41H43N2O8
[M þ NH4]þ 691.3019; found: 691.3015.
white solid. [
a
]25D ¼ þ15.6 (c ¼ 3.5, CHCl3). 1H NMR (400 MHz,
CDCl3)
d
7.88e7.86 (m, 1H), 7.41e7.37 (m, 1H), 7.34e7.19 (m, 22H),
7.08e7.06 (m, 2H), 4.92 (pseudo s, 2H), 4.85 (d, J ¼ 10.8 Hz,1H), 4.79
(d, J ¼ 10.5 Hz, 1H), 4.65e4.49 (m, 5H), 4.06 (t, J ¼ 9.3 Hz, 1H), 3.83
(t, J ¼ 8.7 Hz, 1H), 3.75 (dd, J ¼ 11.0, 1.6 Hz, 1H), 3.69e3.62 (m, 3H),
(4-(Trifluoromethyl)phenyl)((2R,3R,4S,5R,6R)-3,4,5-
tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-
yl)methanone (9). This compound was synthesized from thioester
1b (30.0 mg, 0.04 mmol) and 4-trifluoromethylphenylboronic acid
(17.0 mg, 0.08 mmol) according to the general procedure. The
product 9 was obtained in 83% yield (26.0 mg) as a white solid. 1H
2.52 (s, 3H); 13C NMR (101 MHz, CDCl3)
d 197.6, 139.4, 138.5, 138.2,
138.0, 136.5, 131.89, 131.87, 129.7, 128.4, 128.3, 128.2, 128.0, 127.9,
127.8, 127.7, 127.6, 127.5, 125.7, 87.0, 80.2, 80.0, 79.4, 78.1, 75.7, 75.1,
75.0, 73.4, 69.0, 21.4. HRMS (ESI) m/z calcd for
C42H46NO6
[M þ NH4]þ 660.3325; found: 660.3318.
NMR (600 MHz, CDCl3)
d
8.14 (d, J ¼ 8.1 Hz, 2H), 7.63 (d, J ¼ 8.2 Hz,
(4-(Benzyloxy)phenyl)((2R,3R,4S,5R,6R)-3,4,5-
2H), 7.36e7.26 (m, 13H), 7.25e7.10 (m, 5H), 7.01 (dd, J ¼ 6.4, 2.9 Hz,
2H), 4.94 (s, 2H), 4.86 (d, J ¼ 10.9 Hz, 1H), 4.75 (d, J ¼ 10.4 Hz, 1H),
4.64e4.56 (m, 3H), 4.56e4.45 (m, 2H), 4.00 (t, J ¼ 9.3 Hz, 1H),
3.89e3.82 (m, 1H), 3.78e3.72 (m, 1H), 3.70e3.64 (m, 3H); 19F NMR
tris(benzyloxy)-6-((benzyloxy)methyl) tetrahydro-2H-pyran-2-
yl)methanone (5). This compound was synthesized from thio-
ester 1b (50.0 mg, 0.07 mmol) and 4-benzyloxybenzeneboronic
acid (34.0 mg, 0.14 mmol) according to the general procedure.
The product 5 was obtained in 89% yield (48.0 mg) as a white solid.
(376 MHz, CDCl3)
d
ꢁ63.2 (s); 13C NMR (151 MHz, CDCl3)
d 193.8,
2
138.3, 138.2, 138.0, 137.8, 137.5, 134.6 (q, JC-F ¼ 32.7 Hz), 129.7,
1H NMR (400 MHz, CDCl3)
d
8.07e8.05 (m, 2H), 7.46e7.15 (m, 23H),
128.50, 128.48, 128.34, 128.26, 128.03, 128.00, 127.9, 127.8, 127.74,
3
1
7.02e6.99 (m, 2H), 6.98e6.95 (m, 2H), 5.11 (pseudo s, 2H), 4.94 (d,
J ¼ 11.0 Hz, 1H), 4.91 (d, J ¼ 11.0 Hz, 1H), 4.85 (d, J ¼ 10.8 Hz, 1H),
4.69 (d, J ¼ 10.3 Hz, 1H), 4.61e4.56 (m, 4H), 4.50 (d, J ¼ 12.1 Hz, 1H),
4.02 (t, J ¼ 9.3 Hz, 1H), 3.84 (t, J ¼ 8.4 Hz, 1H), 3.78e3.65 (m, 4H).
The spectroscopic data coincide with the previous report [11c].
(3,4-Dimethoxyphenyl)((2R,3R,4S,5R,6R)-3,4,5-
tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-
yl)methanone (6). This compound was synthesized from thioester
1b (30.0 mg, 0.04 mmol) and 3,4-dimethoxyphenylboronic acid
(16.0 mg, 0.08 mmol) according to the general procedure. The
product 6 was obtained in 61% yield (19.0 mg) as a white soild. 1H
127.67, 125.5 (q, JC-F ¼ 3.8 Hz), 123.56 (q, JC-F ¼ 272.8 Hz), 87.0,
80.0, 79.5, 79.2, 77.9, 75.8, 75.2, 75.0, 73.4, 68.9. HRMS (ESI) m/z
calcd for C42H39O6F3Na [M þ Na]þ 719.2596; found: 719.2606.
[1,1′-Biphenyl]-4-yl((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-
((benzyloxy)methyl) tetrahydro-2H-pyran-2-yl)methanone (10).
This compound was synthesized from thioester 1b (30.0 mg,
0.04 mmol) and 4-phenylbenzeneboronic acid (18.0 mg,
0.08 mmol) according to the general procedure. The product 10 was
obtained in 88% yield (27.5 mg) as a white solid. 1H NMR (400 MHz,
CDCl3)
d 8.15e8.13 (m, 2H), 7.65e7.60 (m, 4H), 7.50e7.25 (m, 16H),
7.21e7.14 (m, 5H), 7.00 (dd, J ¼ 6.6, 3.2 Hz, 2H), 4.97e4.91 (m, 2H),
4.86 (d, J ¼ 11.0 Hz, 1H), 4.74e4.66 (m, 2H), 4.63e4.50 (m, 4H), 4.08
(t, 1H), 3.87 (t, J ¼ 7.0 Hz, 1H), 3.80e3.68 (m, 4H). The spectroscopic
data coincide with the previous report [11c].
NMR (400 MHz, CDCl3)
d
7.74 (dd, J ¼ 8.5, 2.0 Hz, 1H), 7.62 (d,
J ¼ 2.0 Hz, 1H), 7.35e7.16 (m, 18H), 7.05e7.02 (m, 2H), 6.79 (d,
J ¼ 8.5 Hz, 1H), 4.95 (d, J ¼ 11.0 Hz, 1H), 4.91 (d, J ¼ 11.0 Hz, 1H), 4.87
(d, J ¼ 10.8 Hz, 1H), 4.71 (d, J ¼ 10.4 Hz, 1H), 4.62e4.53 (m, 4H), 4.51
(d, J ¼ 12.0 Hz, 1H), 4.04 (t, J ¼ 9.3 Hz, 1H), 3.92 (s, 3H), 3.87e3.81
(m, 1H), 3.86 (s, 3H), 3.77 (d, J ¼ 9.9 Hz, 1H), 3.71e3.67 (m, 3H). The
spectroscopic data coincide with the previous report [11c].
(2-(4-methoxybenzyl)phenyl)((2R,3R,4S,5R,6R)-3,4,5-
tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-
yl)methanone (11). This compound was synthesized from thio-
ester 1b (1.00 g, 1.5 mmol) and (2-(4-methoxybenzyl)phenyl)
boronic acid 2e (0.72 g, 3.0 mmol) according to the general pro-
cedure. The product 11 was obtained in 88% yield (0.98 g) as a white
Ethyl
4-((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzy-
loxy)methyl)tetrahydro-2H-pyran-2-carbonyl) benzoate (7).
This compound was synthesized from thioester 1b (100.0 mg,
0.15 mmol) and 4-ethoxycarbonylphenylboronic acid (58.0 mg,
0.30 mmol) according to the general procedure. The product 7 was
solid. [
a
]25D ¼ þ19.0 (c ¼ 1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
d
7.85 (dd, J ¼ 7.9, 1.4 Hz, 1H), 7.41e7.15 (m, 21H), 7.08e7.05 (m, 4H),
6.76e6.73 (m, 2H), 4.91 (pseudo s, 2H), 4.84 (d, J ¼ 10.8 Hz,1H), 4.77
(d, J ¼ 10.5 Hz, 1H), 4.61e4.46 (m, 5H), 4.22e4.14 (m, 2H), 4.05 (t,
J ¼ 9.2 Hz, 1H), 3.82 (t, J ¼ 8.8 Hz, 1H), 3.75e3.72 (m, 1H), 3.73 (s,
obtained in 84% yield (87.0 mg) as a white solid. [
d 8.12e8.06 (m, 4H),
7.36e7.26 (m, 13H), 7.23e7.15 (m, 5H), 7.04e7.01 (m, 2H), 4.93
a
]25D ¼ þ40.0
(c ¼ 0.5, CHCl3). 1H NMR (400 MHz, CDCl3)
3H), 3.68e3.57 (m, 3H); 13C NMR (101 MHz, CDCl3)
d 197.9, 157.8,
7

L.-N. Wang, Y.-H. Niu, Q.-H. Cai et al.
Tetrahedron 82 (2021) 131955
142.2, 138.5, 138.2, 138.0, 136.7, 132.8, 131.8, 131.4, 130.2, 129.5,
128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.65, 127.63, 127.60, 127.5,
126.0, 113.7, 87.0, 80.2, 80.1, 79.3, 78.1, 75.6, 75.1, 74.9, 73.4, 69.1,
55.2, 38.1. HRMS (ESI) m/z calcd for C49H52NO7 [M þ NH4]þ
766.3744; found: 766.3745.
(E)-3-Phenyl-1-((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-
((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)prop-2-en-1-one
(12). This compound was synthesized from thioester 1b (30.0 mg,
0.04 mmol) and 2-phenylethenylboronic acid (12.0 mg, 0.08 mmol)
according to the general procedure. The product 12 was obtained in
80% yield (23.0 mg) as a white solid. 1H NMR (400 MHz, CDCl3)
4-((2R,3R,4S,5S,6R)-3,4,5-Tris(benzyloxy)-6-((benzyloxy)
methyl)tetrahydro-2H-pyran-2-carbonyl)benzonitrile (16). This
compound was synthesized from thioester 1c (30.0 mg, 0.04 mmol)
and 4-cyanophenylboronic acid (13.0 mg, 0.08 mmol) according to
the general procedure. The product 16 was obtained in 77% yield
(22.4 mg) as a white solid. [
(400 MHz, CDCl3)
a
]25D ¼ ꢁ16.5 (c ¼ 1.8, CHCl3). 1H NMR
d
8.16e8.13 (m, 2H), 7.51e7.48 (m, 2H), 7.40e7.23
(m, 15H), 7.17e7.14 (m, 3H), 7.10e7.05 (m, 2H), 5.02 (d, J ¼ 11.2 Hz,
1H), 4.83e4.74 (m, 3H), 4.61 (d, J ¼ 11.1 Hz, 1H), 4.56 (d, J ¼ 10.6 Hz,
1H), 4.46 (d, J ¼ 11.8 Hz, 1H), 4.43e4.33 (m, 3H), 4.06 (d, J ¼ 2.5 Hz,
1H), 3.75e3.70 (m, 2H), 3.58 (d, J ¼ 6.3 Hz, 2H); 13C NMR (101 MHz,
d
7.73 (d, J ¼ 16.1 Hz, 1H), 7.51e7.49 (m, 2H), 7.42e7.18 (m, 23H),
CDCl3) d 193.3, 138.5, 138.0, 137.9, 137.7, 137.6, 132.0, 130.1, 128.54,
7.01 (d, J ¼ 16.0 Hz, 1H), 4.94 (d, J ¼ 11.1 Hz, 1H), 4.90 (d, J ¼ 11.1 Hz,
1H), 4.84 (d, J ¼ 10.8 Hz, 1H), 4.72 (d, J ¼ 10.4 Hz, 1H), 4.63e4.55 (m,
4H), 4.13e4.08 (m, 1H), 3.83e3.66 (m, 5H), 3.60e3.56 (m, 1H). The
spectroscopic data coincide with the previous report [10].
128.46, 128.40, 128.3, 128.2, 128.0, 127.93, 127.89, 127.84, 127.82,
127.7, 127.6, 118.1, 116.2, 84.4, 82.0, 78.0, 75.2, 75.0, 74.6, 73.6, 73.4,
72.4, 68.8. HRMS (ESI) m/z calcd for C42H43N2O6 [M þ NH4]þ
671.3121; found: 671.3117.
Furan-2-yl((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzy-
loxy)methyl)tetrahydro-2H-pyran-2-yl)methanone (13). This
compound was synthesized from thioester 1b (30.0 mg,
0.04 mmol) and 2-furanboronic acid (10.0 mg, 0.08 mmol) ac-
cording to the general procedure. The product 13 was obtained in
70% yield (19.0 mg) as a white solid. 1H NMR (400 MHz, CDCl3)
(2,4-Difluorophenyl)((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-
6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methanone
(17). This compound was synthesized from thioester 1c (30.0 mg,
0.04 mmol) and 2,4-difluorophenylboronic acid (14.0 mg,
0.08 mmol) according to the general procedure. The product 17 was
obtained in 90% yield (27.0 mg) as a white solid. 1H NMR (600 MHz,
d
7.63 (dd, J ¼ 1.7, 0.7 Hz,1H), 7.39 (dd, J ¼ 3.6, 0.8 Hz,1H), 7.34e7.27
CDCl3) d 8.00e7.94 (m, 1H), 7.37e7.15 (m, 20H), 6.88e6.83 (m, 1H),
(m, 13H), 7.20e7.17 (m, 5H), 7.05e7.02 (m, 2H), 6.51 (dd, J ¼ 3.6,
1.7 Hz, 1H), 4.94 (d, J ¼ 11.0 Hz, 1H), 4.90 (d, J ¼ 11.1 Hz, 1H), 4.84 (d,
J ¼ 10.8 Hz, 1H), 4.68 (d, J ¼ 10.4 Hz, 1H), 4.60e4.50 (m, 4H), 4.45 (d,
J ¼ 9.6 Hz, 1H), 3.94 (t, J ¼ 9.3 Hz, 1H), 3.82 (t, J ¼ 8.9 Hz, 1H),
3.76e3.59 (m, 4H). The spectroscopic data coincide with the pre-
vious report [10].
6.78e6.72 (m, 1H), 4.97 (d, J ¼ 11.4 Hz, 1H), 4.89 (d, J ¼ 10.3 Hz, 1H),
4.80e4.71 (m, 3H), 4.62 (d, J ¼ 11.5 Hz, 1H), 4.47e4.33 (m, 4H), 4.01
(d, J ¼ 2.8 Hz, 1H), 3.75e3.71 (m, 2H), 3.56 (d, J ¼ 6.4 Hz, 2H); 19F
NMR (376 MHz, CDCl3)
d
ꢁ101.5 (dd, J ¼ 12.7 Hz), ꢁ105.4 (d,
J ¼ 12.8 Hz); 13C NMR (151 MHz, CDCl3)
d
191.27 (d, 3JC-F ¼ 4.0 Hz),
165.9 (dd, 1JC-F ¼ 257.2, 3JC-F ¼ 12.4 Hz), 162.81 (dd, 1JC-F ¼ 260.1, 3JC-
3
3
(2-(Methylthio)phenyl)((2R,3R,4S,5R,6R)-3,4,5-
¼ 12.5 Hz), 138.5, 138.3, 138.2, 137.8, 133.42 (dd, JC-F ¼ 10.5, JC-
¼ 3.8 Hz), 128.5, 128.4, 128.3, 128.2, 128.14, 128.12, 127.9, 127.80,
F
F
tris(benzyloxy)-6-((benzyloxy)methyl) tetrahydro-2H-pyran-2-
yl)methanone (14). This compound was synthesized from thio-
ester 1b (30.0 mg, 0.04 mmol) and 2-(methylthio)phenylboronic
acid (15.0 mg, 0.08 mmol) according to the general procedure. The
product 14 was obtained in 92% yield (27.6 mg) as a pale yellow
2
4
127.78, 127.75, 127.63, 127.59, 127.57, 121.33 (dd, JC-F ¼ 11.7, JC-
2
4
2
¼ 3.5 Hz), 111.88 (dd, JC-F¼21.3, JC-F ¼ 3.3 Hz), 104.80 (dd, JC-
¼ 27.7, 2JC-F ¼ 25.3 Hz), 84.7, 81.7, 81.6, 78.4, 75.6, 75.3, 74.5, 73.5,
F
F
73.4, 72.5, 68.9. HRMS (ESI) m/z calcd for C41H42F2NO6 [M þ NH4]þ
682.2980; found: 682.2991.
solid. [
d
a
]25D ¼ þ25.0 (c ¼ 0.6, CHCl3). 1H NMR (600 MHz, CDCl3)
7.95 (t, J ¼ 1.8 Hz, 1H), 7.84 (dt, J ¼ 7.8, 1.3 Hz, 1H), 7.48e7.46 (m,
(4-Methoxyphenyl) ((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-
((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methanone (18).
This compound was synthesized from thioester 1c (30.0 mg,
0.04 mmol) and 4-methoxyphenylboronic acid (14.0 mg,
0.08 mmol) according to the general procedure. The product 18 was
obtained in 84% yield (25.0 mg) as a white solid. 1H NMR (400 MHz,
1H), 7.37e7.26 (m, 15H), 7.23e7.21 (m, 4H), 7.07e7.05 (m, 2H), 4.93
(pseudo s, 2H), 4.85 (d, J ¼ 10.8 Hz, 1H), 4.72 (d, J ¼ 10.4 Hz, 1H),
4.64e4.61 (m, 3H), 4.58 (d, J ¼ 12.1 Hz, 1H), 4.53 (d, J ¼ 12.1 Hz, 1H),
4.03 (t, J ¼ 9.3 Hz, 1H), 3.85 (t, J ¼ 8.2 Hz, 1H), 3.79e3.67 (m, 4H),
2.46 (s, 3H); 13C NMR (151 MHz, CDCl3)
d 194.5, 139.6, 138.4, 138.0,
137.9, 137.7, 136.3, 131.4, 128.8, 128.5, 128.4, 128.3, 128.2, 128.03,
127.98, 127.9, 127.74, 127.69, 127.6, 126.4, 126.0, 87.0, 80.1, 79.5, 79.3,
78.0, 75.8, 75.2, 75.0, 73.4, 68.9, 15.6. HRMS (ESI) m/z calcd for
CDCl3) d 8.13e8.09 (m, 2H), 7.39e7.24 (m, 15H), 7.20e7.16 (m, 3H),
7.10e7.08 (m, 2H), 6.82e6.78 (m, 2H), 5.03 (d, J ¼ 11.4 Hz, 1H), 4.80
(d, J ¼ 11.8 Hz, 1H), 4.76e4.72 (m, 2H), 4.64 (d, J ¼ 11.5 Hz, 1H), 4.57
(d, J ¼ 10.3 Hz, 1H), 4.48e4.39 (m, 4H), 4.05 (d, J ¼ 2.7 Hz, 1H), 3.83
(s, 3H), 3.75e3.70 (m, 2H), 3.61e3.59 (m, 2H); 13C NMR (101 MHz,
C
42H46NO6S [M þ NH4]þ 692.3046; found: 692.3037.
1-(3-((2R,3R,4S,5S,6R)-3,4,5-Tris(benzyloxy)-6-((benzyloxy)
methyl)tetrahydro-2H-pyran-2-carbonyl)phenyl)ethan-1-one
(15). This compound was synthesized according to the general
procedure using 2,3,4,6-tetra-O-benzyl-b-D-galactopyranosyl thio-
ester 1c (50.0 mg, 0.07 mmol) and 3-acetylphenylboronic acid
(15.0 mg, 0.14 mmol) as substrates. The desired product 15 was
CDCl3) d 193.1, 163.6, 138.8, 138.3, 138.1, 137.9, 132.0, 128.50, 128.45,
128.40, 128.3, 128.2, 128.1, 127.94, 127.89, 127.8, 127.7, 127.5, 113.6,
84.4, 81.3, 78.0, 76.2, 75.1, 74.4, 73.61, 73.59, 72.5, 69.0, 55.4. HRMS
(ESI) m/z calcd for C42H46NO7 [M þ NH4]þ 676.3274; found:
676.3282.
obtained in 83% yield (41.0 mg) as a white solid. [
a
]25D ¼ ꢁ4.5
(2,3,4-Trimethoxyphenyl)((2R,3R,4S,5S,6R)-3,4,5-
(c ¼ 3.3, CHCl3). 1H NMR (400 MHz, CDCl3)
d
8.60 (t, J ¼ 1.8 Hz, 1H),
tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-
yl)methanone (19). This compound was synthesized from thio-
ester 1c (30.0 mg, 0.04 mmol) and 2,3,4-trimethoxyphenylboronic
acid (19.0 mg, 0.08 mmol) according to the general procedure. The
desired product 19 was obtained in 88% yield (28.0 mg) as a white
8.29 (dt, J ¼ 7.8, 1.5 Hz, 1H), 8.10 (dt, J ¼ 7.8, 1.5 Hz, 1H), 7.43e7.22
(m, 16H), 7.16e7.07 (m, 5H), 5.01 (d, J ¼ 11.3 Hz, 1H), 4.82e4.74 (m,
3H), 4.64 (d, J ¼ 11.3 Hz, 1H), 4.58 (d, J ¼ 10.6 Hz, 1H), 4.47e4.39 (m,
4H), 4.06 (d, J ¼ 2.6 Hz, 1H), 3.78e3.74 (m, 2H), 3.63e3.55 (m, 2H),
2.43 (s, 3H); 13C NMR (101 MHz, CDCl3)
d
197.5, 193.9, 138.5, 138.1,
solid. [
a
]25D ¼ ꢁ14.9 (c ¼ 0.9, CHCl3). 1H NMR (400 MHz, CDCl3)
137.8, 137.7, 137.2, 135.4, 134.0, 132.3, 129.8, 128.8, 128.5, 128.4,
128.32, 128.27, 128.2, 128.1, 127.89, 127.85, 127.79, 127.76, 127.63,
127.59, 84.4, 82.0, 78.1, 75.5, 75.0, 74.8, 73.8, 73.6, 72.6, 68.9, 26.4.
HRMS (ESI) m/z calcd for C43H46NO7 [M þ NH4]þ 688.3274; found:
688.3277.
d
7.40e7.27 (m, 18H), 7.18e7.10 (m, 5H), 4.97 (d, J ¼ 11.0 Hz, 1H),
4.81 (d, J ¼ 11.8 Hz, 1H), 4.77 (d, J ¼ 11.8 Hz, 1H), 4.72 (d, J ¼ 10.8 Hz,
1H), 4.59 (d, J ¼ 11.0 Hz, 1H), 4.53 (d, J ¼ 10.7 Hz, 1H), 4.50e4.40 (m,
3H), 4.28 (d, J ¼ 9.8 Hz, 1H), 4.06 (d, J ¼ 2.7 Hz, 1H), 3.87 (s, 3H),
3.74e3.69 (m, 2H), 3.62e3.69 (m, 2H), 3.59 (s, 6H); 13C NMR
8

L.-N. Wang, Y.-H. Niu, Q.-H. Cai et al.
Tetrahedron 82 (2021) 131955
(101 MHz, CDCl3)
d
193.5, 152.7, 142.6, 138.4, 138.2, 137.8, 137.7,
(m, 2H), 4.03 (t, J ¼ 9.5 Hz,1H), 3.78 (t, J ¼ 3.6 Hz, 2H), 3.79e3.72 (m,
129.9, 128.53, 128.49, 128.45, 128.41, 128.3, 128.1, 127.94, 127.88,
127.8, 127.63, 127.58, 107.1, 84.4, 83.7, 77.9, 75.9, 75.3, 74.8, 74.4,
73.6, 72.7, 68.9, 60.8, 55.9. HRMS (ESI) m/z calcd for C44H50NO9
[M þ NH4]þ 736.3486; found: 736.3484.
3H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3)
d 197.8, 143.7, 138.5,
138.3, 138.2, 138.1, 133.6, 130.2, 128.7, 128.44, 128.36, 128.33, 128.27,
128.1, 128.00, 127.95, 127.7, 127.61, 127.59, 127.4, 127.3, 84.2, 83.8,
79.8, 76.0, 75.3, 74.9, 74.6, 73.4, 72.2, 69.5, 21.7. HRMS (ESI) m/z
calcd for C42H46NO6 [M þ NH4]þ 660.3325; found: 660.3325.
(4-Methoxyphenyl)((2S,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-6-
methyltetrahydro-2H-pyran-2-yl)methanone (24). This com-
pound was synthesized from 1f (30.0 mg, 0.04 mmol) and 4-
methoxyphenylboronic acid (16.0 mg, 0.08 mmol) according to
the general procedure. The product 24 was obtained in 93% yield
(4-Isopropylphenyl)((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-
((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methanone (20).
This compound was synthesized from thioester 1e (30.0 mg,
0.04 mmol) and 4-isopropylbenzeneboronic acid (14.0 mg,
0.08 mmol) according to the general procedure. The product 20 was
obtained in 91% yield (27.0 mg) as a white solid. [
a
]25D ¼ þ29.6
(c ¼ 1.2, CHCl3). 1H NMR (400 MHz, CDCl3)
d
7.96e7.94 (m, 2H),
(27.0 mg) as a white solid. [
(400 MHz, CDCl3) d 8.08e8.04 (m, 2H), 7.37e7.26 (m, 10H),
a
]25D ¼ þ31.7 (c ¼ 2.3, CHCl3). 1H NMR
7.39e7.11 (m, 22H), 5.17 (d, J ¼ 2.8 Hz, 1H), 4.83 (d, J ¼ 10.9 Hz, 1H),
4.78 (d, J ¼ 12.4 Hz, 1H), 4.73 (d, J ¼ 12.4 Hz, 1H), 4.68 (d, J ¼ 11.8 Hz,
1H), 4.63 (d, J ¼ 11.8 Hz, 1H), 4.55 (d, J ¼ 12.0 Hz, 1H), 4.48 (d,
J ¼ 10.9 Hz, 1H), 4.45 (t, J ¼ 2.9 Hz, 1H), 4.39 (d, J ¼ 12.0 Hz,1H), 4.00
(t, J ¼ 9.0 Hz, 1H), 3.87 (dd, J ¼ 8.9, 3.0 Hz, 1H), 3.73 (dd, J ¼ 10.9,
5.3 Hz, 1H), 3.64e3.55 (m, 2H), 2.95e2.88 (m, 1H), 1.25e1.21 (m,
7.18e7.13 (m, 3H), 7.10e7.07 (m, 2H), 6.88e6.84 (m, 2H), 4.97 (d,
J ¼ 10.8 Hz, 1H), 4.75e4.66 (m, 4H), 4.46 (d, J ¼ 11.3 Hz, 1H),
4.40e4.36 (m, 2H), 3.86 (s, 3H), 3.76e3.68 (m, 2H), 3.47e3.40 (m,
1H), 1.43 (d, J ¼ 6.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 196.2,
163.4, 138.4, 138.2, 138.1, 132.3, 129.0, 128.44, 128.39, 128.14, 128.11,
128.0, 127.72, 127.69, 127.6, 127.4, 113.3, 84.1, 83.7, 80.1, 76.3, 76.2,
75.6, 74.6, 72.1, 55.4, 18.3. HRMS (ESI) m/z calcd for C35H37O6 [M þ
H]þ 553.2590; found: 553.2592.
6H); 13C NMR (101 MHz, CDCl3)
d 198.8, 155.2, 138.42, 138.36, 138.3,
132.9, 129.5, 128.4, 128.34, 128.27, 128.2, 128.0, 127.8, 127.7, 127.65,
127.58, 127.5, 127.4, 126.5, 80.2, 78.0, 76.1, 74.8, 74.71, 73.4, 73.1,
72.5, 72.3, 69.4, 34.3, 23.6, 23.5. HRMS (ESI) m/z calcd for C44H50NO6
[M þ NH4]þ 688.3638; found: 688.3640.
(4-tert-Butoxylcarbonylaminophenyl)((2S,3R,4R,5S,6S)-3,4,5-
tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)methanone
(25). This compound was synthesized from thioester 1f (30.0 mg,
0.04 mmol) and 4-(Boc-amino)phenylboronic acid (16.0 mg,
0.08 mmol) according to the general procedure. The product 25 was
(4-Methoxyphenyl)((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-
((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methanone (21).
This compound was synthesized from thioester 1e (30.0 mg,
0.04 mmol) and 4-methoxyphenylboronic acid (14.0 mg,
0.08 mmol) according to the general procedure. The product 21 was
obtained in 84% yield (28.0 mg) as a white solid. [
a
]25D ¼ þ13.5
(c ¼ 3.8, CHCl3). 1H NMR (400 MHz, CDCl3)
d 8.02e7.98 (m, 2H),
obtained in 85% yield (25.0 mg) as a white solid. [
a
]25D ¼ þ32.4
7.39e7.27 (m, 12H), 7.18e7.14 (m, 3H), 7.12e7.08 (m, 2H), 6.67 (s,
1H), 4.97 (d, J ¼ 10.8 Hz, 1H), 4.74e4.65 (m, 4H), 4.46 (d, J ¼ 11.4 Hz,
1H), 4.42e4.36 (m, 2H), 3.75e3.67 (m, 2H), 3.46e3.40 (m, 1H), 1.53
(c ¼ 1.9, CHCl3). 1H NMR (400 MHz, CDCl3)
d 8.04e8.02 (m, 2H),
7.40e7.22 (m, 18H), 7.15e7.12 (m, 2H), 6.82e6.80 (m, 2H), 5.14 (d,
J ¼ 2.7 Hz,1H), 4.84 (d, J ¼ 10.9 Hz,1H), 4.78 (d, J ¼ 12.4 Hz,1H), 4.73
(d, J ¼ 12.3 Hz, 1H), 4.69 (d, J ¼ 11.7 Hz, 1H), 4.64 (d, J ¼ 11.7 Hz, 1H),
4.54e4.47 (m,3H), 4.39 (d, J ¼ 11.9 Hz, 1H), 3.98 (t, J ¼ 9.0 Hz, 1H),
3.90e3.87 (m, 1H), 3.81 (s, 3H), 3.73 (dd, J ¼ 11.0, 5.5 Hz, 1H), 3.62
(dd, J ¼ 10.9, 2.2 Hz, 1H), 3.55e3.51 (m, 1H); 13C NMR (101 MHz,
(s, 9H), 1.42 (d, J ¼ 6.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 196.2,
152.1, 142.8, 138.4, 138.2, 138.1, 131.4, 130.5, 128.43, 128.38, 128.1,
128.0, 127.71, 127.69, 127.6, 127.4, 117.0, 84.1, 83.4, 81.3, 80.0, 76.21,
76.15, 75.6, 74.6, 72.1, 28.3, 18.2. HRMS (ESI) m/z calcd for
C
39H44NO7 [M þ H]þ 638.3118; found: 638.3127.
CDCl3)
d
197.6, 163.9, 138.46, 138.42, 138.40, 138.3, 131.7, 128.4,
(4-(Methoxymethyl)phenyl)((2R,3R,4R,5S,6S)-3,4,5-
128.33, 128.27, 128.2, 128.05, 127.95, 127.8, 127.7, 127.63, 127.57,
127.5, 127.4, 113.6, 80.4, 78.1, 76.0, 74.9, 74.8, 73.4, 73.1, 72.6, 72.2,
69.5, 55.4. HRMS (ESI) m/z calcd for C42H43O7 [M þ H]þ 659.3002;
found: 659.3005.
tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)methanone
(26). This compound was synthesized from thioester 1g (30.0 mg,
0.04 mmol) and 4-(methoxymethyl)phenylboronic acid (17.0 mg,
0.08 mmol) according to the general procedure. The product 26 was
Phenyl((2R,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)
methyl)tetrahydro-2H-pyran-2-yl)methanone (22). This com-
pound was synthesized from thioester 1d (30.0 mg, 0.04 mmol) and
phenylboronic acid (12.0 mg, 0.08 mmol) according to the general
procedure. The product 22 was obtained in 92% yield (26.0 mg) as a
obtained in 90% yield (27.0 mg) as a white solid. [
a
]25D ¼ ꢁ23.5
(c ¼ 1.8, CHCl3). 1H NMR (400 MHz, CDCl3)
d
7.99 (d, J ¼ 7.9 Hz, 2H),
7.40e7.24 (m, 17H), 5.05 (d, J ¼ 2.6 Hz, 1H), 4.90 (d, J ¼ 10.9 Hz, 1H),
4.83e4.64 (m, 4H), 4.59 (d, J ¼ 10.9 Hz, 1H), 4.50e4.47 (m, 3H), 3.82
(dd, J ¼ 9.1, 3.1 Hz, 1H), 3.63 (t, J ¼ 9.1 Hz, 1H), 3.42 (s, 3H),
3.33e3.26 (m, 1H), 1.22 (d, J ¼ 6.1 Hz, 1H); 13C NMR (101 MHz,
white solid. [
CDCl3)
a
]25D ¼ ꢁ9.5 (c ¼ 1.7, CHCl3). 1H NMR (400 MHz,
d
8.12e8.01 (m, 2H), 7.54e7.46 (m, 1H), 7.39e7.07 (m, 22H),
CDCl3) d 199.3, 144.3, 138.5, 138.3, 134.2, 129.3, 128.41, 128.35,128.3,
4.92 (d, J ¼ 10.9 Hz, 1H), 4.78 (d, J ¼ 6.9 Hz, 1H), 4.75 (d, J ¼ 7.5 Hz,
1H), 4.70 (d, J ¼ 11.8 Hz, 1H), 4.62 (d, J ¼ 9.0 Hz, 1H), 4.61e4.51 (m,
3H), 4.50 (d, J ¼ 11.3 Hz, 1H), 4.43 (dd, J ¼ 2.9, 1.3 Hz, 1H), 4.41 (d,
J ¼ 1.3 Hz, 1H), 4.04 (t, J ¼ 9.5 Hz, 1H), 3.78e3.73 (m, 3H), 3.58e3.54
128.0, 127.9, 127.8, 127.7, 127.60, 127.58, 127.1, 80.5, 80.2, 78.6, 75.2,
74.0, 73.5, 73.1, 72.9, 72.2, 58.5, 18.3. HRMS (ESI) m/z calcd for
C
36H39O6 [M þ H]þ 567.2747; found: 567.2743.
(4-(Methoxycarbonylmethyl)phenyl)((2R,3R,4R,5S,6S)-3,4,5-
(m, 1H); 13C NMR (101 MHz, CDCl3)
d
198.6, 138.6, 138.4, 138.21,
tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)methanone
(27). This compound was synthesized from thioester 1g (30.0 mg,
0.04 mmol) and 4-(methoxycarbonylmethyl)phenylboronic acid
(16.0 mg, 0.08 mmol) according to the general procedure. The
product 27 was obtained in 87% yield (27.0 mg), as a white solid.
138.18, 136.2, 132.8, 130.2, 128.5, 128.4, 128.3, 128.1, 128.02, 127.99,
127.9, 127.74, 127.70, 127.6, 127.5, 127.4, 84.3, 84.0, 80.0, 76.2, 75.3,
74.9, 74.8, 73.4, 72.3, 69.6. HRMS (ESI) m/z calcd for C41H44NO6
[M þ NH4]þ 646.3182; found: 646.3169.
p-Tolyl((2R,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)
methyl)tetrahydro-2H-pyran-2-yl)methanone (23). This com-
pound was synthesized from thioester 1d (30.0 mg, 0.04 mmol) and
4-tolylboronic acid (12.0 mg, 0.08 mmol) according to the general
procedure. The product 23 was obtained in 80% yield (23.0 mg) as a
[
a
]25D ¼ ꢁ28.2 (c ¼ 0.9, CHCl3). 1H NMR (400 MHz, CDCl3)
d 7.97 (d,
J ¼ 8.2 Hz, 2H), 7.40e7.23 (m, 17H), 5.04 (d, J ¼ 2.5 Hz, 1H), 4.90 (d,
J ¼ 10.9 Hz, 1H), 4.81 (d, J ¼ 12.4 Hz, 1H), 4.75e4.64 (m, 3H), 4.59 (d,
J ¼ 10.9 Hz, 1H), 4.46 (t, J ¼ 2.8 Hz, 1H), 3.82 (dd, J ¼ 9.1, 3.1 Hz, 1H),
3.71 (s, 3H), 3.68 (s, 2H), 3.63 (t, J ¼ 9.1 Hz, 1H), 3.35e3.28 (m, 1H),
white solid. [
CDCl3)
a
]25D ¼ ꢁ11.9 (c ¼ 2.1, CHCl3). 1H NMR (400 MHz,
1.23 (d, J ¼ 6.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 199.1, 171.1,
d
7.99 (d, J ¼ 8.0 Hz, 2H), 7.37e7.10 (m, 22H), 4.92 (d,
139.8, 138.5, 138.4, 138.3, 133.9, 129.44, 129.40, 128.42, 128.36,
128.3, 128.0, 127.9, 127.8, 127.7, 127.6, 80.5, 80.2, 78.6, 75.1, 73.5,
J ¼ 10.9 Hz, 1H), 4.77e4.68 (m, 2H), 4.67e4.46 (m, 5H), 4.42e4.39
9

L.-N. Wang, Y.-H. Niu, Q.-H. Cai et al.
Tetrahedron 82 (2021) 131955
72.9, 72.3, 52.2, 41.2, 18.3. HRMS (ESI) m/z calcd for C37H42NO7
[M þ NH4]þ 612.2961; found: 612.2968.
KHCO3 (25.0 mg, 0.25 mmol) and DIPEA (75.0 mL, 0.40 mmol) were
added. After the reaction was refluxed at 70 ꢀC for 5 days, the
mixture was concentrated in vacuum and the residue was purified
by column chromatography on silica gel (petroleum ether/ethyl
acetate, 10:1) to afford 30 (8.7 mg, 92%) as a white solid.
3.4. Further product modification
2-((2-(4-Methoxybenzyl)phenyl)difluoromethyl)
[
d
a
]25D ¼ þ47.5 (c ¼ 0.4, CHCl3). 1H NMR (400 MHz, CDCl3)
7.38e7.18 (m, 19H), 7.00 (d, J ¼ 8.5 Hz, 2H), 6.71 (d, J ¼ 8.6 Hz, 2H),
(2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-
tetrahydro-2H-pyran (28). Compound 11 (25.0 mg, 0.033 mmol)
was dissolved in DAST (0.15 mL, 0.60 mmol). The reaction mixture
was heated to 80 ꢀC for 24 h. Additional DAST (0.15 mL, 0.60 mmol)
was then added and the mixture was heated at 80 ꢀC for additional
24 h. The third portion of DAST (0.15 mL, 0.60 mmol) was added and
the reaction was kept at 80 ꢀC for another 24 h. The reaction was
then quenched with sat. NaHCO3, and the mixture was extracted
with CH2Cl2 for three times. The combined organic extract was
washed with brine, dried over Na2SO4 and concentrated in vacuum.
The residue was purified by column chromatography on silica gel
(petroleum ether: ethyl acetate ¼ 20 : 1, v/v) to afford 28 (15.4 mg,
5.53 (d, J ¼ 2.9 Hz, 1H), 4.81 (d, J ¼ 11.2 Hz, 1H), 4.67 (d, J ¼ 11.2 Hz,
1H), 4.60 (d, J ¼ 12.1 Hz, 1H), 4.56e4.49 (m, 3H), 4.22 (dd, J ¼ 6.6,
3.0 Hz, 1H), 4.10e4.07 (m, 1H), 3.99 (s, 2H), 3.93 (dd, J ¼ 8.9, 6.5 Hz,
1H), 3.87e3.80 (m, 2H), 3.68 (s, 3H); 13C NMR (101 MHz, CDCl3)
d
192.6, 157.9, 150.9, 140.7, 138.1, 138.0, 137.8, 137.5, 132.5, 130.5,
130.4, 130.3, 128.44, 128.41, 128.36, 127.9, 127.82, 127.81, 127.74,
127.70, 127.6, 125.4, 113.8, 112.8, 77.8, 76.3, 74.0, 73.6, 73.5, 71.2,
67.9, 55.1, 37.9. HRMS (ESI) m/z calcd for C42H44NO6 [M þ NH4]þ
658.3169; found: 658.3180.
Declaration of competing interest
60%) as a yellow solid. [
(600 MHz, CDCl3)
a
]25D ¼ þ26.2 (c ¼ 2.1, CHCl3). 1H NMR
d
7.58 (d, J ¼ 7.5 Hz, 1H), 7.33e7.11 (m, 23H),
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
7.00e6.97 (m, 2H), 6.78e6.74 (m, 2H), 4.93e4.78 (m, 5H), 4.57 (d,
J ¼ 10.8 Hz, 1H), 4.36 (d, J ¼ 12.1 Hz, 1H), 4.28e4.22 (m, 2H), 4.09 (d,
J ¼ 16.2 Hz, 1H), 3.96 (t, J ¼ 9.1 Hz, 1H), 3.83e3.75 (m, 1H), 3.75 (s,
3H), 3.67 (t, J ¼ 8.9 Hz, 1H), 3.59e3.52 (m, 3H), 3.16e3.13 (m, 1H);
Acknowledgments
19F NMR (376 MHz, CDCl3)
d
ꢁ95.2 (d, J ¼ 258.7 Hz), ꢁ105.2 (d,
J ¼ 258.4 Hz); 13C NMR (151 MHz, CDCl3)
d 157.8, 139.1 (d, JC-
3
This work was financially supported by the grants from the
National Key Research and Development Program of China
(2018YFA0507602), the National Natural Science Foundation of
China (21738001, 91853122), and the Beijing Outstanding Young
Scientist Program (BJJWZYJH01201910001001).
2
2
¼ 3.8 Hz), 138.5, 138.3, 138.05, 137.98, 133.9 (dd, JC-F ¼ 24.2, JC-
F
F
¼ 22.6 Hz), 133.3, 131.9, 129.83, 129.78, 128.44, 128.40, 128.30,
128.25, 128.22, 127.9, 127.8, 127.74, 127.72, 127.62, 127.60, 127.45,
3
3
1
127.42, 127.1 (dd, JC-F ¼ 11.5, JC-F ¼ 7.4 Hz), 125.8, 121.7 (dd, JC-
¼ 246.6, 1JC-F ¼ 251.1 Hz), 113.7, 86.8, 79.4, 79.2 (d, 2JC- F ¼ 32.5, 2JC-
F
¼ 28.3 Hz), 78.2 (d, 3JC-F ¼ 3.3 Hz), 77.7, 75.8, 75.0, 73.4, 68.8, 55.2,
F
Appendix A. Supplementary data
37.7. HRMS (ESI) m/z calcd for C49H52NO6F2 [M þ NH4]þ 788.3763;
found: 788.3770.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.131955.
(S)-(2-(4-Methoxybenzyl)phenyl)((2S,3R,4S,5R,6R)-3,4,5-
tris(benzyloxy)-6-((benzyloxy)methyl)-tetrahydro-2H-pyran-2-yl)
methanol (29). To a solution of compound 11 (30.0 mg, 0.04 mmol)
in dry CH2Cl2/MeOH (3.0 mL, 1/2), NaBH4 (18.0 mg, 0.48 mmol) was
added at 0 ꢀC under argon atmosphere. The solution was warmed
up to room temperature and stirred for 30 min. After completion,
the reaction was quenched with saturated NH4Cl. The mixture was
extracted with CH2Cl2 for three times. Then the combined
dichloromethane phase was washed with brine, dried over Na2SO4
and concentrated in vacuum. The crude product was purified by
flash column chromatography on silica gel (petroleum ether: ethyl
acetate ¼ 20 : 1, v/v) to afford 29 (32.0 mg, 95%) as a colorless oil.
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768.3922.
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