Mild cu(Otf)2-mediated C-glycosylation with chelation-assisted picolinate as a leaving group

Article abstract of DOI:10.1021/acs.joc.0c01041

C-Glycosylation reactions of glycosyl picolinates with allyltrimethylsilane or silyl enol ethers were developed. Picolinate as a chelation-assisted leaving group could be activated by Cu(OTf)₂ and avoided the use of harsh Lewis acids. The glycosylations were operated under mild neutral conditions and gave the corresponding C-glycosides in up to 95% yield with moderate to excellent stereoselectivities.

Full text of DOI:10.1021/acs.joc.0c01041

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Note
Mild Cu(OTf)2-mediated C-glycosylation with
Chelation-Assisted Picolinate as a Leaving Group
Wenjing Ye, Christopher M. Stevens, Peng Wen, Christopher J. Simmons, and Weiping Tang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01041 • Publication Date (Web): 20 Jul 2020
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The Journal of Organic Chemistry
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Mild Cu(OTf)2-mediated C-glycosylation with Chelation-Assisted
Picolinate as a Leaving Group
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Wenjing Ye,a,ǂ,† Christopher M. Stevens,a,ǂ Peng Wen,a,ǂ Christopher J. Simmons,a,b Weiping Tanga,b*
a
School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA
Phone: (608) 890-1846; Fax: (608) 262-5345; E-mail: wtang@pharmacy.wisc.edu
b
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
ǂ
These authors contributed equally.
†
Current address: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University,
Ministry of Education, Shenyang, 110016 Liaoning, China
ABSTRACT: C-glycosylation reactions of glycosyl picolinates with allyltrimethylsilane or silyl enol ethers were
developed. Picolinate as a chelation-assisted leaving group could be activated by Cu(OTf)2 and avoided the use of
harsh Lewis acids. The glycosylations were operated under mild neutral conditions and gave the corresponding C-
glycosides in up to 95% yield with moderate to excellent stereoselectivities.
Glycosylation is arguably the most important reaction in
carbohydrate chemistry and numerous glycosylation protocols
have been developed for the synthesis of glycosides.1 Compared
with O-glycosides, which are susceptible to enzymatic
degradation, C-glycosides have attracted widespread attention
due to their higher stability to glycosidases and hydrolases.2 For
example, The C-glycoside analogue 1 of KRN7000 showed
more effective activity than the corresponding O-glycoside.3
Glycoconjugate 2 of genistein exhibited higher antiproliferative
potential than the parent compound.4 Various natural products
also bear C-glycosidic units, such as (+)-varitriol5 and (+)-
ambruticin S (Figure 1).6 However, among the diverse
glycosylation methods, O-glycosylations occupy a large
majority, and C-glycosylations are comparatively less.2 There
have been various reported methods for the formation of C-
glycosides, including transition metal catalysis and other
catalyst systems,7 Knoevenagel condensations,8 and direct
nucelophilic substitutions.9 While these reactions are efficient,
they are limited in scope of products and tend to rely on harsh
reaction conditions. Considering the C-glycosides as
biologically significant molecules, prevalent to many natural
products, and hydrolytically stable surrogates of native O-
glycosides, it is necessary to develop efficient and
stereoselective C-glycosylation methods under mild conditions
for satisfying the demands of C-glycoside diversity. Of
particular interest is the development of high-yielding and low-
cost methods that can be run under mild conditions that are
compatible to a variety of functional groups.
thioglycosides, lactols, and acetals.10 The most common leaving
group utilized, however, is the acetyl group and other ester-
derivatives, because they are readily available.11 While the
acetyl group has been used effectively as a donor to produce
high yields in short time frames, it requires promotion by air-
Figure 1. Bioactive and natural C-glycosides.
Scheme 1. Glycosylation with isoquinoline carboxylate or
picolinate as a leaving group.
Another consideration in the synthesis of C-glycosides are
the leaving group. Many leaving groups have been utilized in
the past with great successes, such as glycals, glycal halides,
and moisture-sensitive Lewis acids which introduces
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limitations in the reaction scope and feasibility. Therefore, it is
Page 2 of 9
Yield of 7a or 7bc)
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5
6
7
8
Entry Donor
Solvent
CH2Cl2
highly desirable to have a proper leaving group that does not
require these strong acids for activation while maintaining the
high yields.
OBn
BnO
1
42%
O
O
BnO
BnO
O
N
2b)
CH2Cl2
82%
5a
Recently, we developed an efficient mild O-glycosylation
method using isoquinoline-1-carboxylate as a leaving group
(Scheme 1),12 which is advantageous over the previously
reported picolinate,13 by minimizing the transesterification
byproducts. Using Cu(OTf)2 as a mediator for remote
activation,14 the isoquinoline ester can be removed to give an
oxocarbenium ion intermediate, which subsequently leads to O-
glycosides with high yields under mild neutral conditions. This
chelation-assisted approach shows promise in preliminary
application to the synthesis of C-glycosides as the isoquinoline
carboxylate and picolinate leaving groups become traceless
leaving groups through two-point chelation to the copper ion.
Based on these results, we envision that various C-glycosides
can also be prepared under mild and neutral conditions using
the same type of leaving group, giving advantages over the
previous methods that use the acetyl leaving group.
3
4b)
CH2Cl2
CH2Cl2
Et2O
46%
95% (99%)d)
trace
OBn
BnO
O
O
BnO
BnO
N
O
5
5b
6
CH3CN
18%
9
OBz
BzO
O
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O
BzO
7b)
CH2Cl2
CH2Cl2
complicated
trace
BzO
N
O
5c
OBz
BzO
O
O
8b)
BzO
BzO
N
O
5d
a) Conditions: 5 (0.1 mmol), allyl TMS (2.0 eq.), Cu(OTf)2 (1.2
eq.), 4A MS (100 mg), solvent (0.5 mL), rt, Ar, 24 h; b) allyl TMS
(6.0 eq.); c) Isolated yields; d) Total yield of α- and β-anomers, α/β
> 20:1.
Allylic group is a useful building block and it allows many
further transformations due to the versatile terminal olefin
functional group. For example, the aforementioned bioactive
and natural molecules can be accessed through olefin
metathesis of allyl glycosides with the suitable alkenes (Figure
1). The introductions of anomeric allyl saccharides were
generally promoted by Lewis acid-activated glycosylations.15
They usually stereoselectively gave -allyl glycosides in
excellent yield. However, air- and moisture-sensitive Lewis
acids, such as BF3·Et2O, TMSOTf, etc. were needed. Recently,
the Yu group accomplished C-glycosylation of glycosyl ortho-
alkynylbenzoates with allyltrimethylsilane or silyl enol ethers
in high yields and stereoselectivities where a milder Lewis acid
Ph3PAuNTf2 was used.16 Sulfoxide, sulfonates, and
hydroxybenzotriazolyl groups were also employed as leaving
groups for improving the yields and stereoselectivities.17 It was
also reported that allylation of benzylidene protected glucose
and mannose could highly stereoselectively give α- and β-C-
glycosides, respectively.18 Herein, we chose highly nucleophilic
and easily functionalized allyl and silyl enol ethers as the
glycosyl acceptor, stable picolinates as the donors, and the mild
Lewis acid Cu(OTf)2 as the mediator to explore C-glycosylation.
First, benzyl-protected galactosyl isoquinoline carboxylate
5a and picolinate 5b were used as the glycosyl donors to
optimize the reaction conditions (Table 1). Using Cu(OTf)2 as
the mediator and CH2Cl2 as the solvent, the reaction of 5a with
allyl TMS gave the corresponding allyl α-C-glycoside 7a in
42% yield (entry 1). Additionally, trace amounts of allyl β-C-
glycoside was observed by TLC analysis. When the amount of
allyl TMS was increased to 6.0 equiv, the yield of 7a was
improved to 82% (entry 2). Under the same conditions, we
compared the results of the glycosylation of benzyl-protected
galactosyl picolinate 5b with those of 5a. In our previous
work,12 O-glycosylation of glycosyl isoquinoline carboxylates
showed better results than picolinates because the nucleophilic
attack of the ester carbonyl group by the alcohol nucleophile in
the former was inhibited. We later found that picolinates and
isoquinoline carboxylates behaved similarly during the
preparation of glycosyl halides, because halides preferentially
reacted with the anomeric carbon over the carbonyl ester.19 In
the case of C-glycosylation, picolinate 5b (entries 3 and 4) is
slightly better than isoquinoline carboxylate 5a (entries 1 and
2). α-C-Glycoside 7a can be prepared in 95% yield with 6.0
equiv allyl TMS (entry 4). The total yield of α- and β-anomers
was 99% and the ratio of α and β anomers was more than 20:1.
When the solvent was changed from CH2Cl2 to Et2O or CH3CN,
no more than an 18% yield of allyl α-C-glycoside 7a was
obtained (entries 5 and 6). For Et2O, little of the starting
material was consumed, indicating that the low yield is likely
due to solubility issues with Cu(OTf)2. For CH3CN, it is
possible that the oxocarbenium intermediate loses a proton, as
will be discussed more with 7o, as most of the starting material
was consumed in the reaction. Disappointingly, the C-
glycosylation of disarmed donors 5c and 5d did not give the
desired allyl C-glycosides. The reaction of perbenzoyl
galactosyl isoquinoline carboxylate 5c with allyl TMS gave a
complex mixture and only trace amounts of desired product was
observed, while the reaction of less reactive 5d gave trace
amounts of products and most of 5d was recovered (entries 7
and 8). This may be attributed to the high activation energy
Table 1. Optimizing C-glycosylation of galactopyranosyl
isoquinoline carboxylate (IQC) and picolinate (Pico) with
allyltrimethylsilane.a
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The Journal of Organic Chemistry
barriers of disarmed saccharides, and the weaker
nucleophilicity of allyl TMS compared to O-nucleophiles.20
picolinate 5h similarly gave α-allyl product 7h in 65% yield
with a α/β ratio of 20:1.
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9
Using the present allylation protocol, allyl 2-deoxy
glycosides were successfully prepared. The allylation of 5i and
5j exclusively gave α anomers 7i and 7j in 53% and 68% yields,
respectively. Exclusive allyl C-glycoside α-7k was obtained in
59% yield for the perbenzyl ribosyl picolinate 5k substrate. For
these perbenzyl monosaccharide substrates, the allylation
showed high α selectivity, which could be well explained
through the conformational preferences of the oxocarbenium
ion intermediate, as well as consideration of steric effects that
developed in the transition states for nucleophilic attack.20 C-
glycosylation with benzylidene protected glucosyl picolinate 5l
and mannosyl picolinate 5m donors were also tested. Allyl C-
glycosides α-7l and α-7m were acquired in 81% and 53% yields,
respectively. The stereoselectivities of these two reactions were
coherent with the allylation of thioglycosides reported in the
literature.18 The ratio of 20:1 for 7l and exclusive α for 7m were
obtained. C-glycosylation of disaccharide donor 5n was also
explored, giving the corresponding allyl C-glycoside α-7n in 69%
yield with a α/β ratio of 8:1.
Using Cu(OTf)2 as the mediator and CH2Cl2 as the solvent,
the reactions of several more disarmed glycosyl donors with
allyl TMS were investigated. Disappointingly, no desired allyl
C-glycosides were obtained. The reaction of acetyl- or pivaloyl
glucosyl picolinate with allyl TMS showed most of the starting
material remained after the reaction. Hydrolysis products were
collected for perbenzoyl ribosyl and perbenzoyl fucosyl
picolinate substrates. The reaction of perbenzoyl-protected
xylosyl picolinate 5o gave a glycal product 7o in 68% yield
without the desired C-glycoside found (Scheme 3).
Considering the slightly better performance of the picolinate
donor for C-glycosylation and the lower price of picolinic acid
than that of isoquinoline carboxylic acid, glycosyl picolinates
were selected as donors for testing the scope of the Cu(OTf)2-
mediated C-glycosylation (Scheme 2). Most of the armed
monosaccharides and disaccharides demonstrated expected
reactivity and the corresponding allyl C-glycosides were
obtained in moderate to excellent yields. The reaction of
perbenzyl glucosyl picolinate 5e with allyl TMS gave an
excellent result and produced the corresponding allyl C-
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Cu(OTf)2
O
O
RO
6a
Allyl TMS (
)
RO
(2)
OPic
CH2Cl2, rt
5e n
-
7e n
-
BnO
BnO
BnO
O
BnO
BnO
BnO
OBn
O
BnO
BnO
O
BnO
BnO
7fa,c
7gb
a
, 98%
, 74% 
7e
, 90% , / > 20 : 1
86%,  = 15:1d
/ = 10:1
/ = 10:1
BnO
BnO
BnO
OBn
BnO
BnO
O
Me
O
O
OBn
OBn
BnO
7hb
, 65% 
7ib
, only , 53%
7jb
, only , 68%
/ = 20 : 1
BnO
Ph
O
O
O
O
Cu(OTf)2 (1.2 eq)
Allyl TMS (6.0 eq.)
O
BnO
BzO
BzO
O
BnO
, 81% 
BzO
BzO
OBn
BnO
7kb
(3)
7la
4A MS
CH2Cl2, rt
BzO
5o
, only , 59%
OPic
OBz
, 68% yield
/ = 20 : 1
BnO
BnO
BnO
7o
O
O
O
BnO
OBn
O
Ph
Scheme 3. Reaction of disarmed saccharide with allyl TMS.
BnO
O
O
BnO
BnO
Silyl enol ethers are highly versatile coupling reagents for
constructing C-C bonds.21 C-glycosylations of picolinate
donors with nucleophilic silyl enol ethers were therefore
explored (Scheme 4). Aromatic silyl enol ether 8a and aliphatic
silyl enol ether 8b were used as acceptors to investigate the
reactivity and selectivity of the glycosylations. Generally, C-
glycosylations with silyl enol ethers showed less
stereoselectivities than those with allyl TMS as the acceptor.
With 1.2 equiv Cu(OTf)2 as the promoter, the reaction of
BnO
, 69% 
7na
7ma
, only , 53%
/ = 8 : 1
Scheme 2. Cu(OTf)2-mediated C-Glycosylation with allyl
TMS as an acceptor. a) Condition A: 5 (0.1 mmol), allyl TMS
(6.0 equiv), Cu(OTf)2 (1.2 equiv), 4A MS (100 mg), CH2Cl2
(0.5 mL), rt, Ar, 16 h; b) Condition B: 5 (0.1 mmol), allyl TMS
(6.0 equiv), Cu(OTf)2 (1.2 equiv), CH2Cl2 (0.5 mL), rt, Ar, 16
h, toluene was used as azeotrope to remove water; c) The yield
is the combined of α and β; d) 1 mmol reaction scale.
perbenzyl
galactopyranosyl
donor
5b
with
1-
styrenyloxytrimethylsilane 8a (1.5 equiv) produced the
corresponding C-glycoside 9a in 93% total yield with the
stereoselectivity of 2.7:1. Exclusive α C-glycoside 9b was
obtained in 90% yield for the glycosylation of glucosyl donor
5e. Again, the scalability of the reaction was demonstrated by
performing the same reaction on 1 mmol scale, with 9b isolated
in 88% yield as a single anomer. Mannosyl C-glycoside 9c was
prepared as a 1.7:1 mixture of anomers in 98% total yield. The
reactions of benzylidene-protected glucosyl donor 5l and
mannosyl donor 5m with 8a gave similar results to the previous
allylations, but showed lower stereoselectivities. The
glucoside α-7e in 90% yield. A small amount of β anomer was
also collected and the ratio of α and β anomers was more than
20:1. Similar results were obtained when the reaction was
scaled up to 1 mmol, which afforded 7e in 86% yield with a
15:1 α/β ratio. Using perbenzyl mannosyl picolinate 5f as the
donor, the reaction gave 7f in 98% total yield with the α/β ratio
of 10:1. The allylation of xylosyl picolinate 5g led to the allyl
C-glycoside α-7g in 74% yield and the ratio of α and β anomers
was also 10:1. C-glycosylation of Bn-protected L-fucosyl
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glycosylations of 5l and 5m led to the corresponding C-
glycosides 9d and 9e in 78% and 51% total yields with α/β
EXPERIMENTAL SECTION
1
2
3
4
5
6
7
8
All reactions in non-aqueous media were conducted under a
positive pressure of dry argon in glassware that had been dried
in oven prior to use unless noted otherwise. Anhydrous
solutions of reaction mixtures were transferred via an oven
dried syringe or cannula. All solvents were dried prior to use
unless noted otherwise. Starting materials were azeotroped with
dry toluene three times the day before use. Thin layer
chromatography was performed using precoated silica gel
plates. Flash column chromatography was performed with silica
gel (40-63 μm). Infrared spectra (IR) were obtained on a Bruker
O
O
Cu(OTf)2
OTMS
O
RO
RO
(4)
+
4A MS
CH2Cl2, rt
R
OPic
R
5b 5e 5f 5l 5m
9a g
-
,
,
,
,
8a b
-
, 1.5 eq.
OBn
BnO
BnO
BnO
BnO
BnO
BnO
OBn
O
BnO
BnO
O
O
O
O
BnO
OBn
O
Ph
Ph
9ca
9aa
Ph
, 98%
, 93%
9
a
9b
, only , 90%
only , 88%b
/ = 1.7 : 1
/ = 2.7 : 1
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Equinox 55 Spectrophotometer. H and 13C nuclear magnetic
1
resonance spectra (NMR) were obtained on a Varian Unity-
Inova 400 MHz or 500 MHz recorded in ppm (δ) downfield of
TMS (δ = 0) in CDCl3 unless noted otherwise. Signal splitting
patterns were described as singlet (s), doublet (d), triplet (t),
quartet (q), quintet (quint), or multiplet (m), with coupling
constants (J) in hertz. High resolution mass spectra (HRMS)
were performed by Analytical Instrument Center at the School
of Pharmacy or Department of Chemistry on an Electron Spray
Injection (ESI) mass spectrometer.
O
O
BnO
OBn
Ph
O
O
BnO
Ph
O
O
O
O
BnO
9da
Ph
Ph
9ea
, 78%
, 51%
/ = 7 : 1
/ = 1 : 13
OBn
BnO
BnO
BnO
BnO
BnO
O
O
O
BnO
BnO
tBu
O
tBu
9ga
, 87%
9fa
, 92%
/ = 4.5 : 1
/ > 20 : 1
General procedure for the synthesis of silyl enol ether.
Silyl enol ether 8a22 and 8b23 were prepared and characterized
according to the literature methods and their spectra were in
accordance with the literature.
Scheme 4. Cu(OTf)2-mediated C-Glycosylation with silyl
enol ether as an acceptor. Reaction conditions: 5 (0.1
mmol), silyl enol ether (1.5 equiv), Cu(OTf)2 (1.2 equiv), 4A
MS (100 mg), CH2Cl2 (0.5 mL), rt, Ar, 16 h. The yield is the
combined of α and β; b) 1 mmol reaction scale.
a)
Synthesis and characterization of isoquinoline and
picolinic glycosyl donors. All isoquinoline and picolinic
glycosyl donors not otherwise specified below were prepared
and characterized in accordance with previous literature.19
ratios of 7:1 and 1:13, respectively. The C-glycosylations with
1-tert-butylvinyloxytrimethylsilane 8b provided the
corresponding 2-carbonyl C-glycosides 9f and 9g in 92% and
87% yield with α/β ratios of 4.5:1 and >20:1, respectively,
which were similar to the results of acceptor 8a.
In conclusion, both picolinates and isoquinoline
carboxylates are convenient leaving groups for glycosylations,
but the former is more suitable for C-glycosylations. With
Cu(OTf)2 as a mediator, C-glycosylations of stable glycosyl
picolinate donors with allyltrimethylsilane or silyl enol ethers
were explored. The allylations of various armed glycosyl
picolinates offered the corresponding C-glycosides in up to
95% yield with excellent stereoselectivities. The reactions
abided by the oxocarbenium ion intermediate mechanism
reported previously.18,20 Disarmed saccharides could not
produce the desired allyl C-glycosides due to low reactivity.
The glycosylations of armed glycosyl picolinates with silyl enol
5a:
isoquinoline-1-carboxylate. To an oven-dried flask was added
commercially available 2,3,4,6-tetra-O-benzyl-α-D-
2,3,4,6-Tetra-O-benzyl-α-D-galactopyranosyl
galactopyranose (1.00 mmol, 540.7 mg), DMAP (0.20 mmol,
24.4 mg), 1-isoquinolinecarboxylic acid (ISQ-COOH) (1.30
mmol, 225.2 mg), EDCI (2.00 mmol, 383.3 mg) and dry DCM
(5.0 mL) under Ar. The reaction was stirred at RT and
monitored by TLC. After the reaction was completed (~12 h),
the solvent was removed under vacuum and the residue was
purified by flash column chromatography (eluent: Hex:EA=5:1,
V/V) to afford 5a (white solid, 650.0 mg, 94% yield). M.P.:
o
100-102 C. Optical rotation: [α]D21 = +7.32 (c 0.205, CHCl3).
1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 8.7 Hz, 1H), 8.63 (d,
J = 5.5 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 5.5 Hz,
1H), 7.72 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.32 (m,
17H), 7.19-7.08 (m, 3H), 5.99 (d, J = 8.0 Hz, 1H), 5.03-4.93
(m, 2H), 4.86 (d, J = 10.9 Hz, 1H), 4.78 (s, 2H), 4.62 (d, J =
11.4 Hz, 1H), 4.47 (q, J = 11.8 Hz, 2H), 4.21 (t, J = 8.9 Hz, 1H),
4.04 (d, J = 2.8 Hz, 1H), 3.86 (t, J = 6.6 Hz, 1H), 3.78-3.58 (m,
3H). 13C{1H}NMR (101 MHz, CDCl3) δ 164.6, 148.2, 141.8,
138.6, 138.4, 138.3, 137.8, 136.8, 130.5, 128.7, 128.4, 128.4,
128.2, 128.1, 128.1, 128.0, 127.8, 127.7, 127.6, 127.5, 127.4,
127.1, 126.8, 126.3, 124.1, 95.8, 82.3, 78.1, 77.2, 75.3, 74.8,
74.5, 73.6, 72.9, 68.1. HRMS (ESI) for C44H41NO7 (M+H),
696.2956 (Calc.), found 696.2951. IR (neat): ν 1743, 1454,
1366, 1215, 1099, 1028, 745, 698, 997.
ethers
exhibited
good
reactivities
but
moderate
stereoselectivities, except for the reaction of perbenzyl glucosyl
picolinate which exclusively gave α-C-glycoside.
An added benefit of the method reported here over those
previously reported is the use of a relatively cheap copper salt.
This decrease in cost while maintaining relatively good yields,
increases the synthetic efficacy. The use of a picolinate ester as
the glycosyl donor brings added benefits, as they are easily
prepared from commercially available picolinic acid and can be
cleaved under mostly neutral conditions. Picolinic acid is also
much cheaper than reagents involved for the formation of many
other glycosyl donors including the tested isoquinoline-1-
carboxylic acid. The above results show that the stable
picolinate group could be a good glycosyl donor to efficiently
synthesize useful C-glycosides under mild reaction conditions.
5j:
3,4,6-Tri-O-benzyl-2-deoxy-D-galactopyranosyl
picolinate. To an oven-dried flask was added commercially
available 3,4,6-tri-O-benzyl-2-deoxy- D-galactopyranose (1.00
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The Journal of Organic Chemistry
mmol, 434.5 mg), DMAP (0.20 mmol, 24.4 mg), picolinate acid
mmol, 383.3 mg) and dry DCM (5.0 mL) under Ar. The reaction
was stirred at RT and monitored by TLC. After the reaction was
completed (~12 h), the solvent was removed under vacuum and
the residue was purified by flash column chromatography
(eluent: Hex:EA=5:1, V/V) to afford 5n (α:β=1.4:1, colorless
syrup, 260.0 mg, 78% yield). Reported as mixture of anomers,
ratio identified through 1H NMR spectroscopy. Optical rotation:
[α]D21 = +52.5 (c 1.01, CHCl3). 1H NMR (400 MHz, CDCl3) δ
8.83 – 8.68 (m, 2H), 8.12 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 7.8
Hz, 1H), 7.78 (td, J = 7.8, 1.7 Hz, 1H), 7.69 (td, J = 7.8, 1.7 Hz,
1H), 7.47 – 7.34 (m, 2H), 7.37 – 7.04 (m, 70H), 6.70 (d, J = 3.6
Hz, 1H), 6.04 (d, J = 6.9 Hz, 1H), 5.78 (d, J = 3.5 Hz, 1H), 5.67
(d, J = 3.6 Hz, 1H), 5.06 (d, J = 11.7 Hz, 1H), 4.96 – 4.78 (m,
12H), 4.71 (d, J = 11.3 Hz, 2H), 4.66 – 4.42 (m, 12H), 4.32 –
4.16 (m, 8H), 4.03 – 3.75 (m, 8H), 3.74 – 3.64 (m, 2H), 3.59 –
3.49 (m, 2H), 3.47 – 3.34 (m, 3H). 13C{1H}NMR (101 MHz,
CDCl3) δ 163.7, 163.6, 150.3, 150.2, 147.7, 147.4, 138.9, 138.9,
138.7, 138.5, 138.4, 138.3, 138.2, 138.1, 138.0, 138.0, 137.9,
137.5, 137.0, 128.5, 128.5, 128.5, 128.4, 128.4, 128.3, 128.3,
128.2, 128.2, 128.1, 128.1, 128.0, 1278.0, 127.9, 127.9, 127.8,
127.8, 127.8, 127.7, 127.7, 127.6, 127.6, 127.5, 127.4, 127.3,
127.3, 126.9, 126.8, 125.7, 125.6, 97.1, 97.1, 95.2, 91.3, 84.9,
82.1, 81.8, 80.7, 79.6, 79.5, 79.4, 77.8, 75.7, 75.2, 75.1, 74.8,
74.5, 74.2, 73.6, 73.6, 73.5, 73.5, 73.4, 73.4, 73.3, 73.1, 72.8,
71.9, 71.2, 71.2, 68.9, 68.6, 68.3. HRMS (ESI) for C67H67NO12
(M+Na), 1100.4561 (Calc.), found 1100.4561. IR (neat): ν
1738, 1585, 1496, 1454, 1362, 1303, 1289, 1244, 1214, 1152,
1069, 1041, 1027, 914, 849, 819, 744, 735, 696, 665.
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3
4
5
6
7
8
(1.30 mmol, 160.0 mg), EDCI (2.00 mmol, 383.3 mg) and dry
DCM (5.0 mL) under Ar. The reaction was stirred at RT and
monitored by TLC. After the reaction was completed (~12 h),
the solvent was removed under vacuum and the residue was
purified by flash column chromatography (eluent: Hex:EA=2:1,
V/V) to afford 5j (α:β=2.3:1, colorless syrup, 420.0 mg, 80%
yield). Reported as mixture of anomers, ratio identified through
1H NMR spectroscopy. Optical rotation: [α]D21 = +35.3 (c 0.575,
1
CHCl3). H NMR (400 MHz, CDCl3) δ 8.79 – 8.74 (m, 2H),
9
8.13 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.84 – 7.77
(m, 2H), 7.45 (m, 2H), 7.39 – 7.21 (m, 30H), 6.58 (d, J = 3.2
Hz, 1H), 5.98 (dd, J = 10.1, 2.4 Hz, 1H), 5.01 – 4.92 (m, 2H),
4.72 – 4.58 (m, 6H), 4.54 – 4.37 (m, 4H), 4.23 – 4.05 (m, 4H),
3.93 (d, J = 2.4 Hz, 2H), 3.81 – 3.52 (m, 4H), 2.61 – 2.37 (m,
2H), 2.31 – 2.16 (m, 2H). 13C{1H}NMR (101 MHz, CDCl3) δ
163.5, 163.1, 150.2, 150.1, 147.9, 147.3, 138.8, 138.7, 138.2,
138.1, 137.9, 137.9, 137.0, 137.0, 129.8, 129.7, 129.7, 128.5,
128.5, 128.5, 128.4, 128.4, 128.4, 128.4, 128.3, 128.2, 128.2,
128.1, 128.0, 128.0, 128.0, 127.9, 127.9, 127.8, 127.8, 127.8,
127.7, 127.6, 127.6, 127.5, 127.4, 127.2, 127.1, 125.7, 125.3,
94.6, 93.8, 75.0, 74.5, 74.5, 74.0, 73.6, 73.6, 72.8, 72.6, 71.6,
70.5, 70.5, 68.8, 68.6, 31.5, 30.2. HRMS (ESI) for C33H33NO6
(M+Na), 562.2200 (Calc.), found 562.2201. IR (neat): ν 1727,
1644, 1585, 1496, 1454, 1438, 1361, 1304, 1279, 1245, 1201,
1146, 1097, 1044, 1026, 992, 891, 844, 817, 745, 696, 665.
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5k: 2,3,5-Tri-O-benzyl-D-ribofuranosyl picolinate. To an
oven-dried flask was added commercially available 2,3,5-tri-O-
benzyl-D-ribofuranose (1.00 mmol, 420.5 mg), DMAP (0.20
mmol, 24.4 mg), picolinate acid (1.30 mmol, 160.0 mg), EDCI
(2.00 mmol, 383.3 mg) and dry DCM (5.0 mL) under Ar. The
reaction was stirred at RT and monitored by TLC. After the
reaction was completed (~12 h), the solvent was removed under
vacuum and the residue was purified by flash column
chromatography (eluent: Hex:EA=5:1, V/V) to afford 5k
(α:β=2.2:1, light yellow syrup, 430.0 mg, 82% yield). Reported
as mixture of anomers, ratio identified through 1H NMR
spectroscopy. Optical rotation: [α]D21 = +30.9 (c 1.14, CHCl3).
1H NMR (400 MHz, CDCl3, TMS) δ 8.86 – 8.69 (m, 2H), 8.06
(dd, J = 29.2, 7.7 Hz, 2H), 7.84 (m, 2H), 7.64 (td, J = 7.7, 1.8
Hz, 2H), 7.55 – 7.23 (m, 30H), 6.55 (s, 1H), 6.38 (d, J = 7.3 Hz,
1H), 5.02 – 4.84 (m, 2H), 4.83 – 4.43 (m, 8H), 4.41 – 4.31 (m,
2H), 4.26 – 4.07 (m, 2H), 3.92 (dd, J = 11.1, 4.6 Hz, 1H), 3.83
(dd, J = 11.1, 3.1 Hz, 1H), 3.77 – 3.62 (m, 3H). 13C{1H}NMR
(101 MHz, CDCl3, TMS) δ 163.7, 163.7, 163.4, 150.1, 150.0,
147.6, 147.5, 139.1, 138.7, 138.2, 138.1, 138.0, 137.9, 137.6,
137.6, 137.4, 136.9, 136.9, 136.9, 128.5, 128.5, 128.5, 128.4,
128.3, 128.3, 128.2, 128.2, 128.0, 127.9, 127.9, 127.9, 127.8,
127.8, 127.7, 127.7, 127.6, 127.6, 127.5, 127.5, 127.4, 127.1,
127.0, 126.8, 126.4, 125.5, 125.4, 100.5, 94.0, 89.9, 81.9, 78.7,
75.2, 74.7, 74.5, 74.5, 74.2, 73.8, 73.3, 72.5, 72.2, 71.6, 71.2,
69.6, 63.2, 58.9. HRMS (ESI) for C32H31NO6 (M+Na),
548.2044 (Calc.), found 548.2040. IR (neat): ν 1736, 1585,
1496, 1454, 1361, 1305, 1284, 1244, 1216, 1071, 1027, 995,
925, 821, 745, 696, 666.
General procedure for the synthesis of C-glycosides with
allyl TMS. Condition A: Picolinic ester (0.10 mmol),
Cu(OTf)2 (1.2 eq, dried under vacuum overnight), and 4Å MS
(about 100.0 mg, dried with hot gun under vacuum for 15 min)
were added to a vial. Then the vial was refilled with Argon.
CH2Cl2 (0.5 mL) and allyl TMS (6.0 equiv) were added with
syringes under Argon. The vial was capped and stirred at rt for
12-30 h until TLC analysis showed the picolinate was
completely converted, usually 16 h. The mixture was purified
through a silica gel column chromatography (Hexane/Ethyl
acetate = 10:1) to give the corresponding C-glycosides.
Condition B: Picolinic ester (0.10 mmol) and toluene (0.30 mL,
as the azeotrope to remove water) were added to 3 mL vial. The
mixture was stirred under vacuum to remove toluene and the
operation was repeated 3 times for removing water as much as
possible. Then dried Cu(OTf)2 (1.2 equiv) was added to the vial
and the vial was refilled with Argon. CH2Cl2 (0.5 mL) and allyl
TMS (6.0 equiv) were added with syringes under Argon. The
vial was capped and stirred at rt for 12-30 h until TLC analysis
showed the picolinate was completely converted, usually 16 h.
The mixture was purified through a silica gel column
chromatography (Hexane/Ethyl acetate = 10:1) to give the
corresponding C-glycosides.
7a: 3-(Tetra-O-benzyl-α-D-galactopyranosyl)-prop-1-
ene. Condition A was used to synthesize compound 7a. Crude
product purified via flash column chromatography (eluent:
Hex:EA=10:1, V/V) to afford 7a (α, colorless oil, 53.0 mg, 95%
yield; β, colorless oil, 2.5 mg, 4% yield). Spectral data are in
accordance with the literature.24
5n: 2,3,4-Tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-α-D-
glucopyranosyl)-D-glucopyranosyl picolinate. To an oven-
dried flask was added commercially available 2,3,4-tri-O-
benzyl-6-O-(2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl)-D-
glucopyranose (1.00 mmol, 973.2 mg), DMAP (0.20 mmol,
24.4 mg), picolinate acid (1.30 mmol, 160.0 mg), EDCI (2.00
7e:
3-(2,3,4,6-Tetra-O-benzyl-α-D-glucopyranosyl)-
prop-1-ene. Condition A was used to synthesize compound 7e.
Crude product purified via flash column chromatography
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(eluent: Hex:EA=10:1, V/V) to afford 7e (α, colorless oil, 51.0
Hex:EA=10:1, V/V) to afford 7k (only α, colorless oil, 26.0 mg,
59% yield). Spectral data are in accordance with the literature.28
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2
3
4
5
6
7
8
mg, 90% yield; β, colorless oil, 2.0 mg, 4% yield). Spectral data
are in accordance with the literature.25 The one mmol scale
reaction was performed following the same procedure. Picolinic
ester 5e (645.8 mg, 1.00 mmol), Cu(OTf)2 (434.0 mg, 1.20
mmol), and activated 4Å MS (600.0 mg) were added to a 25 mL
round bottom flask. Then the flask was refilled with Argon.
CH2Cl2 (3.0 mL) and allyl TMS (685.6 mg, 6.00 mmol) were
added with syringes under Argon. The reaction mixture was
stirred at rt for 17 h before it was filtered through a pad of Celite.
The filtrate was concentrated under reduced pressure. Flash
column chromatography (eluent: Hex:EA=10:1, V/V) afford 7e
as a colorless oil (484.6 mg, 86% yield, :=15:1).
7l: 2,3-Di-O-benzyl-4,6-O-benzylidene-1-deoxy-1-allyl-
D-glucopyranose. Condition A was used to synthesize
compound 7l. Crude product purified via flash column
chromatography (eluent: Hex:EA=10:1, V/V) to afford 7l (α,
white solid, 38.0 mg, 81% yield; α:β=20:1). Spectral data are in
accordance with the literature.18a
9
7m: 2,3-Di-O-benzyl-4,6-O-benzylidene-1-deoxy-1-allyl-
α-D-mannopyranose. Condition A was used to synthesize
compound 7m. Crude product purified via flash column
chromatography (eluent: Hex:EA=10:1, V/V) to afford 7m
(only α, colorless oil, 25.0 mg, 53% yield). Spectral data are in
accordance with the literature.18a
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7f:
3-(2,3,4,6-Tetra-O-benzyl-α-D-mannopyranosyl)-
prop-1-ene. Condition A was used to synthesize compound 7f.
Crude product purified via flash column chromatography
(eluent: Hex:EA=10:1, V/V) to afford 7f (α:β=10:1, colorless
oil, 55.0 mg, 98% total yield). Spectral data are in accordance
with the literature.25
7n: 2,3,4-Tris-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-α-
D-glucopyranosyl)-1-deoxy-1-allyl-D-glucopyranose.
Condition A was used to synthesize compound 7n. Crude
product purified via flash column chromatography (eluent:
Hex:EA=10:1, V/V) to afford 7n (α, colorless oil, 60.0 mg, 69%
yield; α:β=8:1, 0.09 mmol scale). The α isomer: Optical
rotation: [α]D21 = +41.2 (c 0.425, CHCl3). 1H NMR (400 MHz,
CDCl3) δ 7.32 – 7.14 (m, 33H), 7.10 (dd, J = 6.9, 2.7 Hz, 2H),
5.88 – 5.73 (m, 1H), 5.57 (d, J = 3.6 Hz, 1H), 5.20 – 5.00 (m,
2H), 4.87 (dd, J = 11.3, 8.2 Hz, 2H), 4.80 – 4.71 (m, 3H), 4.64
– 4.39 (m, 8H), 4.28 (d, J = 12.2 Hz, 1H), 4.10 (dt, J = 10.3, 4.8
Hz, 1H), 4.02 (t, J = 8.3 Hz, 1H), 3.95 – 3.86 (m, 2H), 3.82 –
3.72 (m, 4H), 3.69 – 3.61 (m, 2H), 3.55 – 3.47 (m, 2H), 3.40
(dd, J = 10.8, 2.0 Hz, 1H), 2.61 – 2.49 (m, 1H), 2.49 – 2.39 (m,
1H). 13C{1H}NMR (101 MHz, CDCl3) δ 138.8, 138.8, 138.5,
138.5, 138.1, 138.1, 138.0, 134.8, 128.4, 128.4, 128.3, 128.3,
128.3, 128.2, 128.1, 127.9, 127.87, 127.85, 127.8, 127.8, 127.7,
127.7, 127.6, 127.5, 127.4, 127.3, 127.3, 126.9, 117.0, 96.9,
82.0, 81.4, 79.6, 79.5, 77.8, 75.5, 75.0, 73.6, 73.5, 73.4, 73.2,
73.0, 72.7, 71.2, 71.0, 69.6, 68.2, 30.7. HRMS (ESI) for
C64H68O10 (M+Na), 1019.4705 (Calc.), found 1019.4681. IR
(neat): ν 1497, 1454, 1360, 1215, 1074, 1027, 916, 745, 697,
666.
7g: 3-(2,3,4-Tri-O-benzyl-D-xylopyranosyl)-prop-1-ene.
Condition B was used to synthesize compound 7g. Crude
product purified via flash column chromatography (eluent:
Hex:EA=10:1, V/V) to afford 7g (α, colorless oil, 33.0 mg, 74%
yield; α:β=10:1). The α isomer: Optical rotation: [α]D21 = +12.6
(c 0.170, CHCl3). 1H NMR (400 MHz, CDCl3, TMS) δ 7.41 –
7.27 (m, 15H), 5.77 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.13 –
4.99 (m, 2H), 4.65 (d, J = 11.9 Hz, 1H), 4.59 (d, J = 7.7 Hz, 4H),
4.51 (d, J = 11.8 Hz, 1H), 3.83 – 3.67 (m, 4H), 3.42 (dd, J = 5.3,
3.7 Hz, 2H), 2.60 – 2.48 (m, 1H), 2.36 (m, 1H). 13C{1H}NMR
(101 MHz, CDCl3, TMS) δ 138.3, 138.3, 135.0, 128.4, 128.4,
128.3, 128.1, 127.9, 127.8, 127.7, 127.7, 116.9, 77.2, 76.4, 75.2,
74.9, 74.8, 73.4, 72.6, 72.1, 64.5, 33.0, 29.7. HRMS (ESI) for
C29H32O4 (M+Na), 467.2193 (Calc.), found 467.2187. IR (neat):
ν 1496, 1454, 1421, 1395, 1361, 1325, 1301, 1280, 1253, 1209,
1087, 1027, 1003, 992, 973, 935, 912, 873, 848, 828, 807, 796,
751, 737, 697, 679.
7h: 3-(2,3,4-Tri-O-benzyl-α-L-fucopyranosyl)-prop-1-
ene. Condition B was used to synthesize compound 7h. Crude
product purified via flash column chromatography (eluent:
Hex:EA=10:1, V/V) to afford 7h (α, colorless oil, 30.0 mg, 65%
yield; α:β=20:1). Spectral data are in accordance with the
literature.26
7o:
1,5-Anhydro-2,3,4-tri-O-benzoyl-D-threo-pent-1-
enitol. Condition A was used to synthesize compound 7o.
Crude product purified via flash column chromatography
(eluent: Hex:EA=10:1, V/V) to afford 7o (white solid, 30.0 mg,
68% yield). Spectral data are in accordance with the literature.29
7i:
3-(3,4,6-Tri-O-benzyl-2-deoxy-D-glucopyranosyl)-
General procedure for the synthesis of C-glycosides with
silyl enol ethers. Picolinic ester (0.10 mmol), Cu(OTf)2 (1.2 eq,
dried under vacuum overnight), and 4Å MS (about 100.0 mg,
dried with hot gun under vacuum for 15 min) were added to a
vial. Then the vial was refilled with Argon. CH2Cl2 (0.5 mL)
and silyl enol ether (1.5 equiv) were added with syringes under
Argon. The vial was capped and stirred at rt for 12-30 h until
TLC analysis showed the picolinate was completely converted,
usually 16 h. The mixture was purified through a silica gel
column chromatography (Hexane/Ethyl acetate=10:1) to give
the corresponding C-glycosides.
prop-1-ene. Condition B was used to synthesize compound 7i.
Crude product purified via flash column chromatography
(eluent: CH2Cl2:Acetone=50:1, V/V) to afford 7i (only α,
colorless oil, 24.0 mg, 53% yield). Spectral data are in
accordance with the literature.27
7j:
3-(3,4,6-Tri-O-benzyl-2-deoxy-α-D-
galactopyranosyl)-prop-1-ene. Condition B was used to
synthesize compound 7j. Crude product purified via flash
column chromatography (eluent: Hex:EA=10:1, V/V) to afford
7j (only α, colorless oil, 31.0 mg, 68% yield). Spectral data are
in accordance with the literature.16
9a:
1-(2,3,4,6-Tetra-O-benzyl-D-galactopyranosyl)-
acetophenone. Crude product purified via flash column
chromatography (eluent: Hex:EA=10:1, V/V) to afford 9a
(α:β=2.7:1, colorless oil, 60.0 mg, 93% total yield). Spectral
data are in accordance with the literature.30
7k:
3-(2,3,5-Tri-O-benzyl-α-D-ribofuranosyl)-prop-1-
ene. Condition B was used to synthesize compound 7k. Crude
product purified via flash column chromatography (eluent:
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9b:
1-(2,3,4,6-Tetra-O-benzyl-α-D-glucopyranosyl)-
44.1, 39.0, 35.8, 29.7, 26.3, 26.1. HRMS (ESI) for C40H46O6
(M+Na), 645.3187 (Calc.), found 645.3173. IR (neat): ν 1704,
1496, 1454, 1367, 1216, 1092, 1028, 911, 746, 696, 667.
1
2
3
4
5
6
7
8
acetophenone. Crude product purified via flash column
chromatography (eluent: Hex:EA=10:1, V/V) to afford 9b (only
α, white solid, 58.0 mg, 90% yield). Spectral data are in
accordance with the literature.16 The 1.0 mmol scale reaction
was performed following the same procedure. Picolinic ester 5e
(645.8 mg, 1.00 mmol), Cu(OTf)2 (434.0 mg, 1.20 mmol), and
activated 4Å MS (600.0 mg) were added to a 25 mL round
bottom flask. Then the flask was refilled with Argon. CH2Cl2
(5.0 mL) and silyl enol ether 8a (288.5 mg, 1.50 mmol) were
added with syringes under Argon. The reaction mixture was
stirred at rt for 7 h before it was filtered through a pad of Celite.
The filtrate was concentrated under reduced pressure. Flash
column chromatography (eluent: Hex:EA=10:1, V/V) afford 9b
as a white solid (567.9 mg, 88% yield, only ).
9g:
3,3-Dimethyl-1-(2,3,4,6-tetra-O-benzyl-α-D-
glucopyranosyl)-butan-2-one. Crude product purified via
flash column chromatography (eluent: Hex:EA=10:1, V/V) to
afford 9g15b (α:β > 20:1, white solid, 54.0 mg, 87% yield).
Spectral data are in accordance with the literature.31
9
ASSOCIATED CONTENT
Supporting Information.
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This material is available free of charge via the Internet at
http://pubs.acs.org
Copies of 1H NMR data
Copies of 13C{1H}NMR data
9c:
1-(2,3,4,6-Tetra-O-benzyl-D-mannopyranosyl)-
acetophenone. Crude product purified via flash column
chromatography (eluent: Hex:EA=10:1, V/V) to afford 9c
(α:β=1.7:1, colorless oil, 63.0 mg, 98% total yield). A small
portion of the anomers was separated. The α isomer: Optical
rotation: [α]D21 = +5.26 (c 0.570, CHCl3). 1H NMR (400 MHz,
CDCl3) δ 7.88 (d, J = 8.1 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.43
(t, J = 7.6 Hz, 2H), 7.37 – 7.17 (m, 20H), 4.78 – 4.71 (m, 1H),
4.65 (dd, J = 11.5, 1.5 Hz, 1H), 4.61 – 4.39 (m, 7H), 3.91 – 3.84
(m, 2H), 3.84 – 3.76 (m, 3H), 3.76 – 3.72 (m, 1H), 3.21 (td, J =
6.5, 1.5 Hz, 2H). 13C{1H}NMR (101 MHz, CDCl3) δ 197.6,
138.4, 138.2, 138.1, 138.1, 137.0, 133.1, 128.6, 128.4, 128.3,
128.3, 128.2, 128.1, 128.0, 127.8, 127.8, 127.7, 127.5, 76.0,
75.3, 74.6, 73.5, 73.4, 71.9, 71.2, 69.1, 68.8, 39.8. HRMS (ESI)
for C42H42O6 (M+Na), 665.2874 (Calc.), found 665.2857. IR
(neat): ν 1682, 1598, 1496, 1453, 1362, 1216, 1093, 1026, 913,
863, 846, 814, 746, 696, 666.
ACKNOWLEDGMENT
We thank the University of Wisconsin-Madison and NIH (U01
GM125290) for financial support.
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9d:
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Reported as mixture of anomers, ratio identified through H
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1
CHCl3). H NMR (400 MHz, CDCl3) δ 7.46 – 7.15 (m, 40H),
4.94 (dd, J = 17.3, 11.6 Hz, 2H), 4.77 – 4.72 (m, 1H), 4.69 –
4.60 (m, 7H), 4.58 – 4.35 (m, 8H), 4.08 – 4.00 (m, 2H), 3.98
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TMS
O
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• C-glycosylation
• Copper assisted
• Mild conditions
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