Reagent-Controlled Divergent Synthesis of C-Glycosides

Article abstract of DOI:10.1021/acs.joc.0c01544

By turning on or switching off the directing effect of the C3-OH-located o-diphenylphosphanylbenzoyl (o-DPPB) group in glycals, a reagent-controlled protocol for divergent and regio- and stereoselective syntheses of C-glycosides has been established. In particular, the silence of the directing effect of o-DPPB was achieved by the introduction of a ZnCl2 additive, which is operationally simple and efficient. The flexibility of the novel protocol was exhibited not only by the easy access of both α- and β-C-glycosides but also by the versatility of the obtained formal Ferrier rearrangement products, which can be easily derivatized to various C-glycoside analogues owing to the embedded multifunctionalities.

Full text of DOI:10.1021/acs.joc.0c01544

Subscriber access provided by CARLETON UNIVERSITY
Article
Reagent-Controlled Divergent Synthesis of C-Glycosides
Pu-Ren Han, Jianchao Liu, Jin-Xi Liao, Yuan-Hong Tu, and Jian-Song Sun
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01544 • Publication Date (Web): 07 Aug 2020
Downloaded from pubs.acs.org on August 7, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 44
The Journal of Organic Chemistry
1
2
3
4
5
Reagent-Controlled Divergent Synthesis of C-Glycosides
6
7
8
9
Pu-Ren Han, Jianchao Liu, Jin-Xi Liao, Yuan-Hong Tu, and Jian-Song Sun*
National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, 99 Ziyang Avenue, Nanchang,
330022, China.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
jssun@jxnu.edu.cn
Graphic abstract:
O
O
O
O
CuBr-SMe2
Et2O
CuBr-SMe2
Et2O
O
R
PPh2
+
MgBr
R
R
-Selectivity

-Selectivity

ZnCl2
ZnCl2
Abstract: Leveraging on the exquisitely turning on or switching off the directing effect of the
C3-OH located o-diphenylphosphanylbenzoyl (o-DPPB) group in glycals, a reagent-controlled
protocol for divergent and regio- and stereo-selective synthesis of C-glycosides has been
established. In particularly, the silence of the directing effect of o-DPPB was achieved by the
introduction of ZnCl2 additive, which is operationally simple and efficient. The flexibility of the
novel protocol was exhibited not only by the easy access of both α- and β-C-glycosides but also by
the versatility of the obtained formal Ferrier rearrangement products, which can be easily
derivatized to various C-glycoside analogues owing to the embedded multi-functionalities.
Introduction
C-Glycosides are featured by attaching of the carbohydrate units to acceptors via carbon
atoms instead of oxygen atoms, which exhibit dramatically enhanced stability toward both acidic
and enzymatic hydrolysis in comparison to their O-congeners. Consequently, they have been
widely applied as surrogates/mimetics of native O-glycosides during the development of novel
biochemical probes and pharmaceuticals.1 Also, as structural subunits C-glycosides occur in a
wide variety of natural products with significant biological activities.2 The biological relevance in
combination with the synthetic challenges associated with C-glycosidic linkage constructions have
been spurring the studies of seeking for highly efficient protocols of C-glycosylation, resulting in
the establishment of diversities of approaches.3 Among all methods, those commencing with
glycals are drawing considerable attention from synthetic chemists owing to the formal Ferrier
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 44
1
2
3
4
rearrangement4 products with multi-functionalities provide valuable handles for
5
6
7
8
after-glycosylation derivatization.5 With glycals as starting materials, four types of reactions have
been devised to secure the formal Ferrier rearrangement products: acid-promoted Ferrier
rearrangements,6 allylic 1,3-substitutions,7 Heck reactions,8 and Tsuji-Trost reactions (Figure 1).9
Nevertheless, some reactions suffer from limited stereo-diversity during the C-glycosydic linkage
construction furnishing α-C-glycosides as the predominating or sole products. Moreover, the
unsatisfactory coupling regioselectivity seriously impairs the synthetic efficiency frequently. Thus,
to facilitate the diversity-oriented synthesis of C-glycosides with high efficiency, a
reagent-controlled protocol to divergently furnish α/β-stereoisomers with full regioselectivity
control is highly desired. In line with our continuous interest in C-glycosides synthesis,10 a
program was launched to pursue such an approach to realize the flexible and efficient synthesis of
α/β C-glycosides.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The glycal allylic 1,3-substitution protocol is appealing as the non-catalyst version has been
devised for the preparation of C-glycosides. However, to make the C-glycosylations proceed
smoothly in the absence of catalyst either glycals with improved reactivity7a,b or organo-metallic
nucleophiles with appropriate Lewis acidity[7c] have to be applied. Meanwhile, the obtained
moderate regio- as well as stereo-selectivity leaves room for further optimization. Inspired by the
seminal work of Breit and co-workers regarding ortho-diphenylphosphanylbenzoyl (o-DPPB)
group-directed, copper-mediated allylic substitution with Grignard reagents (o-DDCMAS
protocol),[11] we assumed that the o-DDCMAS method, after being modified according to the
special glycal substrates, may find applications in stereoselective synthesis of C-glycosides.
Moreover, theoretically, the divergency of the novel protocol can be achieved by switching on or
turning off the directing effect of o-DPPB group to afford either syn-SN2’ or anti-SN2’ products,
respectively, potentially overcoming the drawbacks associate with existing glycal allylic
1,3-substitution protocols for the preparation of C-glycosides (Figure 1).
ACS Paragon Plus Environment

Page 3 of 44
The Journal of Organic Chemistry
1
2
3
4
Ferrier rearrangement
:
5
6
O
O
O
1
Nu
Lewis acid
Nu
Nu
O
7
8
9
- X
2
3
X
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Allylic 1,3-substitution
O
O
X
O
Nu
Nu
Nu
NuX
or
- X
X
Heck reaction:
O
Nu
PdLn
O
O
Nu
Nu-PdLn
- X or H
migratory
insertion
-elimination
X
X
R
Tsuji-Trost reaction:
O
O
O
Nu
PdLn
Nu
PdLn
- X
X
This work: reagent controlled divergent allylic 1,3-substitution
O
O
Directing effect
Directing effect RO
O
R
turn off
switch on
+
R
R MgBr
-Selectivity

-Selectivity

R = Directing Group = o-diphenylphophanylbenzyl group(o-DPPB)
Figure 1. Various protocols for the synthesis of C-glycosides.
Results and discussion
The investigation started with the model coupling between 1a12 and methylmagnesium
bromide 2a (Table 1). Pleasantly, when treated with the identical conditions as those devised by
Breit et al.,[11] the desired methyl-C-glycoside 3aa were obtained β-stereoselectively in a moderate
40% yield accompanied by 15% yield of C-3 methylation isomer 4aa as a mixture of α/β-isomers
(α/β = 1 : 1). The exclusive formation of β-3aa verifying that the expected directing effect of
o-DPPB group can indeed be exploited to forge β-C-glycoside, while the formation of 4aa as a
mixture of α/β-isomers indicates that the regio-byproduct was generated via a carbon-cationic
intermediate. The reaction was proved to be highly temperature sensitive, and the synthetic
efficiency of 3aa as well as the regioselectivity of the coupling reaction dropped dramatically
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 44
1
2
3
4
5
6
7
8
9
when the reaction temperature varied (entries 2-5). Low temperature (-20 oC) largely halted the
reaction leading to the detection of only trace amounts of 3aa and 4aa by TLC (entry 4); on the
contrary high temperature (40 oC) compromised the regioselectivity seriously (almost 1 : 1 of 3aa
and 4aa were isolated, entry 5). Besides ethyl ether, other ether-type solvents including THF,
1,4-dioxane, and MTBE were also checked under otherwise identical conditions, but inferior
results were recorded in terms of yields and regioselectivity (entries 6-8). Although THF and
dioxane provided extremely scrambled mixtures, the MTBE indeed afforded 3aa but as the minor
product in comparison to its C3-isomer, indicating that the MTBE solvent could reverse the
regioselectivity of glycal allylic 1,3-substitution reaction from C1 to C3 to provide 4aa as the
major product (34% and 45% yield for 3aa and 4aa, respectively, entry 8). In order to further
improve the synthetic efficiency of 3aa while suppressing the formation of 4aa, the applied
amounts of Cu(I) and Grignard reagent were adjusted systematically (entries 9-16). Upon varying
only one parameter, either the amount of copper catalyst (from 0.5 to 1.0 equivalents) or the
amount of Grignard reagent (from 1.5 to 1.0 equivalents), deleterious effects on the coupling
reaction were observed since diminished stereoselectivity (for 3aa) and regioselectivity were
obtained (entries 9 and 10). Thus, changing the two parameters simultaneously was then
investigated (entries 11-16), and finally found that under the combined effect of 1.0 equivalent of
copper catalyst and 2.0 equivalents of Grignard reagent the optimal results were obtained (β-3aa
was isolated in 59% yield and no C-3 isomer 4aa was isolated, entry 12). Efforts to further
optimize the coupling reaction entailed increasing copper catalyst from 1.0 to 2.0 equivalents and
Griganard reagent form 2.0 to 4.5 equivalents. However, unfortunately, only deteriorated results,
as compared to the results of entry 12, were obtained (entries 13-16). Although the result that no
reaction was detected in the absence of Cu(I) catalyst obtained in a control reaction fully
demonstrates that copper salt is indispensable in the coupling reaction (entry 17), other copper
salts, such as CuCl, CuBr, CuI, Cu(OAc)2, as well as Cu(acac)2, only presented inferior results
with respect to the chemical yields and regioselectivity of the couplings (entries 18-22).
Interestingly, similar to the solvent effect of MTBE, Cu(OAc)2 and Cu(acac)2 also biased the
formation of the C3-regioisomer 4aa (entries 21 and 22).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Optimization of the conditions for the synthesis of β-C-glycosides.
ACS Paragon Plus Environment

Page 5 of 44
The Journal of Organic Chemistry
1
2
3
4
O
O
O
Me
O
2a
MeMgBr ( ), [Cu]
O
O
5
6
7
+
Et2O, Temp
PMB
O
PMB
O
PMB
O
Me
O(o-DPPB)
4aa
3aa
1a
8
9
Entry
1
[Cu] (eq)
MeMgBr (eq)
Temp (oC)
30
3aaa (α/β)b
4aac
15%
11%
11%
trace
28%
NDe
NDe
45%
15%
8%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CuBr•SMe2 (0.5)
CuBr•SMe2 (0.5)
CuBr•SMe2 (0.5)
CuBr•SMe2 (0.5)
CuBr•SMe2 (0.5)
CuBr•SMe2 (0.5)
CuBr•SMe2 (0.5)
CuBr•SMe2 (0.5)
CuBr•SMe2 (0.5)
CuBr•SMe2 (1.0)
CuBr•SMe2 (1.0)
CuBr•SMe2 (1.0)
CuBr•SMe2 (1.0)
CuBr•SMe2 (1.5)
CuBr•SMe2 (1.5)
CuBr•SMe2 (2.0)
--
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
1.5
1.0
2.0
3.0
3.0
4.5
4.0
2.0
2.0
2.0
2.0
2.0
40% (only β)
25% (only β)
10% (only β)
trace
2
23
3
0
4
-20
40
5
32% (only β)
NDe
6d
7f
30
30
NDe
8g
9
30
34% (only β)
25% (1 : 5)
38% (1 : 4.3)
30% (1 : 3.2)
59% (only β)
39% (only β)
23% (only β)
30% (only β)
34% (1 : 3.2)
NDe
30
10
11
12
13
14
15
16
17
18
19
20
21
22
30
30
25%
NDe
15%
15%
5%
30
30
30
30
30
23%
NDe
6%
30
CuCl (1.0)
30
28% (only β)
40% (only β)
42% (only β)
31% (only β)
CuBr (1.0)
30
23%
5%
CuI (1.0)
30
Cu(OAc)2 (1.0)
30
40%
40%
Cu(acac)2 (1.0)
2.0
30
23% (1 : 2.5)
aIsolated yield. a/β ratios were determined by H NMR. Isolated yield. THF was used as solvent.eND = Not
b
1
c
d
Detected. f1.4-Dioxane was used as solvent. gMTBE was used as solvent.
With the optimal conditions in hand, the substrate scope was then checked with different
glycals and various Grignard reagents (Table 2). As with the methylmagnesium bromide 2a, ethyl
and propyl Grignard reagents 2b and 2c also react with 1a to furnish 3ab and 3ac β-selectively
(54% and 55% yield, respectively). The di-tert-butylsilylene (DTBS) group was tolerated as a
protecting group in the glucal substrate, and the condensation between 1b and 2a-c provided
3ba-bc with excellent stereoselectivity (50%, 48%, and 55% yield). The desired
β-stereoselectivity was maintained even with glucal 1c in an opened 4,6-O-protecting pattern.
Thus, upon treatment of 1c with 2a-b, the β-3ca and β-3cb were formed exclusively (46% for 3ca
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 44
1
2
3
4
5
6
7
8
9
and 44% for 3cb). In addition, the galactal derivative 1e was also a competent substrate to
participate in C-glycosylation reactions with 2a-b, affording 3ea and 3eb β-selectively (3ea: 42%
and 3eb: 40%). The excellent β-stereoselectivity of the tested couplings demonstrates the
robustness of the directing effect of o-DPPB group, relying on which the reactions proceed
through a syn-SN2’ mechanism. The moderate synthetic efficiency results from the deacylation of
the glycal substrates, which has been observed previously but to less extent in simply
functionalized substrates.13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Phenyl Grignard reagent 2d could also be used as a nucleophile to react with 1a-d to give
phenyl C-glycosides 3ad-dd; however, only marginal β-stereoselectivity was secured. Similar
problem has been encountered previously, and can be explained by the less nucleophilicity of
aryl-Grignard reagents, which retards the directing group-involved syn-SN2’ process while
accordingly favors the anti-SN2’ substitution to deliver α-C-glycosides.13,14 All configuration of
newly formed C-glycosydic linkages were unequivocally determined by NOE experiments,
wherein evident correlations between H-1 and H-5 were observed.12,15
Table 2. The substrate scope investigation for the β-C-glycosylation protocol.a
O
O
R
R1O
R2O
CuBr SMe2 R1O
Et2O
R-MgBr
+
R2O
2a
2b
2c
2d
R = Me
R = Et
R = Pr
R = Ph
O(o-DPPB)
3
1a
1b
1c
1d
1e
R1, R2 = PMB
R1, R2 = DTBS
R1 = R2 = Bn
Glucal
R1, R2 = isopropyl
Galactal
R1, R2 = MPP ---
O
Me
O
O
Me
O
Et
O
nPr
Me
O
O
O
tBu Si
O
tBu
PMB
O
PMB
3ab
O
PMB
O
3aa
, 59%,  only
3ba
, 50%,  only
, 54%,  only
nPr
3ac
, 55%,  only
O
O
O
Et
O
O
Et
BnO
BnO
O
BnO
tBu Si
tBu Si
O
tBu
BnO
O
tBu
3cb
, 44%,  only
3bc
, 55%,  only
3ca
, 46%,  only
3bb
, 48%,  only
O
Me
O
O
Et
O
PMB
O
PMB
O
3eb
, 40%,  only
3ea
, 42%,  only
O
Ph
O
Ph
O
O
Ph
O
Ph
O
O
BnO
BnO
tBu Si
PMB
3ad
O
O
O
tBu
3bd
, 40%,  = 4:5
3cd
, 40%,  = 1:2.5
3dd
, 45%,  = 3:5
, 43%,  = 1:2
aReaction conditions unless otherwise noted: 1 (0.2 mmol), CuBr•SMe2 (0.2 mmol), RMgBr (0.4 mmol), Et2O (4
mL), N2 atmosphere, 30 oC, 7-8 h. Isolated yield and the a/β ratios were determined by 1H NMR.
ACS Paragon Plus Environment

Page 7 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
With the optimal conditions for preparation of β-C-glycosides settled, our attention was then
turned to the generation of α-C-glycosides. Theoretically, upon silencing the directing effect of the
o-DPPB group, then the formation of α-C-glycosides could be achieved through an anti-SN2’
mechanism. Keeping the aim of seeking reagent-controlled protocols for C-glycosides synthesis in
mind, we decided to devise a novel approach different from the Breit’s method,11 which inevitably
requires an extra step of o-DPPB group oxidation, to turn off the directing effect of o-DPPB group.
In fact, the oxidative method of Breit’s group was also checked; however, no desired
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
C-glycosylation product were obtained, and the only detectable compounds from the reaction
system were unchanged and deacylated 1a (Table 3, entry 1). Besides o-DPPB, another frequently
investigated directing group in allylic 1,3-substitution is picoloyl (Pico) group.16 The directing
effect of Pico group is achieved by coordinating with MgBr2 in situ generated during the
formation of organocopper reagents rather than directly steering the attacking approach of
nucleophiles by complexing with organocopper species. Similarly, in our case an anti-SN2’
substitution mechanism can be exploited to prepare α-C-glycosides. As for o-DPPB group, the
complexing affinity between MgBr2 and phosphorus atom is rather low, laying a foundation for
the establishment of the above discussed β-selective C-glycosylation method. To blocking the
chelating phosphorus atom, ZnCl2 was tried as an additive since ZnI2 has been used to improve the
regioselctivity of Pico group-involved allylic 1,3-substitution.17 Under otherwise the identical
conditions to the optical ones for β-C-glycosidic linkage construction, 0.5 equivalents of ZnCl2
successfully reversed the glycosylation stereoselectivity of 1a and 2a from β only to
α-predominantly (α/β = 3.5 : 1) albeit with moderate yield and unsatisfactory regioselectivity
(24% yield of 3aa, entry 2). The synthetic efficiency was shown to be highly additive dependent
with 1.5 equivalents of ZnCl2 affording the highest yield and satisfactory regioselectivity (88%
yield of 3aa and no 4aa was detected, entry 4). Either reducing or raising the applied amounts of
ZnCl2 adversely affected the transformations both in yield and in regioselectivity (entries 3 and 5).
Interestingly, the stereoselectivity was maintained (above 3 : 1 of α/β ratios) no matter how many
equivalents of ZnCl2 were added (entries 3-5). Although ZnBr2 also provided good yield of 3aa,
however, the stereoselectivity and the regioselectivity of the reaction eroded (84%, α/β = 2.5 : 1,
entry 6). On the contrary, the choice of ZnI2 as an additive brought about evident decrease in
chemical yield of 3aa while keeping the stereo- and regio-selectivity unchanged (59% yield, α/β =
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 44
1
2
3
4
5
6
7
8
9
3.5 : 1, entry 7). Replacing ZnCl2 with AlCl3 completely destroyed the regioselctivity of the
coupling reaction, leading to the formation of 3aa and 4aa with a ratio of 1 : 1 (entry 8). Attempts
to further optimize the reaction by screening different Cu(I) salts, including CuCl, CuBr, and CuI,
in the presence of ZnCl2 uniformly met with failure, and no better results than those listed in entry
4 were recorded (entries 9-11). Cu(II) salts, such as Cu(OAc)2 and Cu(acac)2, did ameliorate the
stereoseletivity to above 4.5 : 1, but the low conversion efficiency combined with the diminished
regioselectivity nullified the improvement in chiral selectivity (entries 12, 13). Finally, the
coupling between 1a and 2a was also conducted in the absence of copper catalyst under the
otherwise identical conditions, but non-regioselectivity as well as compromised yield was
observed (entry 14). However, the obtained α/β ratio (4 : 1) comparable to that of the optimal
conditions reveals that the chelation of Zn(II) with o-DPPB directing group does not bias the
formation of β-C-glycosides via a similar mechanism as that used for copper catalyst in the
absence of ZnCl2 additive.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Optimization of conditions for the synthesis of a-C-glycosides.
O
O
Me
O
2a
MeMgBr
[Cu], Et2O, 30 o
O(o-DPPB)
(2.0 eq)
O
O
O
+
C
PMB
O
PMB
O
PMB
O
Me
3aa
4aa
1a
Entry
1d
2
[Cu] (1.0 eq)
Additive (eq)
--
3aaa (α/β)b
NDe
4aac
trace
11%
23%
NDe
8%
CuBr•SMe2
CuBr•SMe2
CuBr•SMe2
CuBr•SMe2
CuBr•SMe2
CuBr•SMe2
CuBr•SMe2
CuBr•SMe2
CuCl
ZnCl2 (0.5)
ZnCl2 (1.0)
ZnCl2 (1.5)
ZnCl2 (2.0)
ZnBr2 (1.5)
ZnI2 (1.5)
AlCl3 (1.5)
ZnCl2 (1.5)
ZnCl2 (1.5)
ZnCl2 (1.5)
ZnCl2 (1.5)
ZnCl2 (1.5)
ZnCl2 (1.5)
24% (3.5 : 1)
52% (3 : 1)
88% (3.2 : 1)
50% (3.5 : 1)
84% (2.5 : 1)
59% (3.5 : 1)
19% (1 : 2)
53% (3.5 : 1)
55% (3.4 : 1)
23% (3.6 : 1)
24% (4.6 : 1)
31% (4.7 : 1)
30% (4 : 1)
3
4
5
6
10%
NDe
20%
8%
7
8
9
10
11
12
13
14
CuBr
23%
10%
6%
CuI
Cu(OAc)2
Cu(acac)2
--
19%
30%
aIsolated yield. bα/β ratios were determined by 1NMR. cIsolated yield. dWith o-DPPB oxide ester
of 1a as glucal substrate. eND = Not Detected.
ACS Paragon Plus Environment

Page 9 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The substrate scope in terms of both glycals and Grignard reagents were evaluated subsequently
(Table 4). In glucal series substrates, those bearing either cyclic or open protecting groups on C4,6
hydroxy groups were well accommodated by the devised α-C-glycosylation protocol (1a-d).
Moreover, apart from alkyl Grignard reagents (2a-c), ArMgBrs could also be used to condense
with glucal-type substrates to forge phenyl C-glycosidic linkages (2d-j). Furthermore, galactals
with different protecting groups were also proved to be viable substrates to react with both alkyl
and aryl Grignard reagents (1e-f), affording α-C-glycosides as the major or predominant products.
In comparison with the alkyl Grignard reagents, the aryl Grignard reagents tend to provide better
α-stereoselectivity, as exemplified by glycal substrates 1c and 1e. In the case of 1c, almost no
stereoselectivity was obtained when alkyl Grignard reagents 2a-b were selected as nucleophiles
(around 1 : 1 of α/β ratios for 3ca and 3cb), while good α-stereoselectivity was recorded for aryl
nucleophiles 2d-e and 2j (above 4.8 : 1 of α/β ratios for 3cd, 3ce, and 3cj). For galactal substrate
1e, alkyl Grignard reagents 2a-b only presented moderate α-stereoselectivity (1.5 : 1 and 3.3 : 1,
respectively, for 3ea and 3eb); however, aryl Grignard reagents 2d-e and 2j provided excellent
α-stereoselectivity when coupled with 1e (only α isomers were formed for 3ed-ee and 3ej ).
Resembling the low stereoselectivity of ArMgBr nucleophiles in β-C-glycosylation, the
stereoselectivity discrepancy between alkyl and aryl Grignard reagents can also be ascribed to the
low nucleophility of aryl Grignard reagents. Influenced by the bulky di-tert-butyl-silylene
protecting group, galactal 1f gave the desired α-C-glycosides exclusively with good yields, no
matter either alkyl or aryl Grignard reagents were applied (above 70% yield for 3fd-fe and 3fh-fj).
Although the low nucleophilicity of aryl Grignard reagents benefit to the α-stereoselectivity of
C-glycosylation, prolonged reaction time and slight heating were frequently required to make the
coupling reactions to proceed with reasonable rates and high yields. The α-configuration of all
α-C-glycosides was established by NOE experiments, and the corresponding correlations between
H-1 and H-5, which have been used to determine the β-stereoisomers, were not detected in the
α-C-glycosides series.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. The substrate scope checking for the α-C-glycosylation protocol.a
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 44
1
2
3
4
5
6
7
8
9
O
R1O
R2O
O
R
CuBr SMe2
ZnCl
R1O
R-MgBr
+
2, Et2O, 30 o
C
R2O
O(o-DPPB)
3aa 3fj
-
2a
2b
2c
2d
2e
R = Me
R = Et
2f
R = 2-MeOPh
R = 3-MeOPh
R = 4-MeOPh
R = 4-MePh
1a
1b
1c
1d
R1, R2 = PMB
R1, R2 = DTBS
R1 = R2 = Bn
2g
2h
Glucal
R = nPr
R = Ph
2i
2j
R1, R2 = isopropyl
R = 2-MePh
R
1 = 4-FPh
1e
1f
R1, R2 = MPP
R1, R2 = DTBS
Galactal
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
R
O
Me
O
R
O
O
O
tBu Si
PMB
O
O
tBu
PMB
O
3ad
3ae
3af
3ag
3ah
, R = Ph, 90%,  = 5.2:1
, R = 2-MePh, 86%,  = 4:1
, R = 2-MeOPh, 66%,  = 3.5:1
, R = 3-MeOPh, 70%,  = 4:1
, R = 4-MeOPh, 75%,  = 5.2:1
, R = 4-FPh, 93%,  = 3.5:1
3ba
, 88%,  = 4.5:1
3aa
3ab
3ac
, R = Me, 88%,  = 3.2:1
, R = Et, 75%,  = 2:1
, R = nPr, 76%,  = 2.5:1
O
R
b
O
b
tBu Si
b
O
tBu
O
R
3aj
BnO
BnO
3bd
3be
3bi
, R = Ph, 74%,  = 4.3:1
, R = 2-MePh, 79%,  = 5.2:1
, R = 4-MePh, 90%,  = 4:1
, R = 4-FPh, 83%,  = 5.6:1
O
R
O
b
3bj
3ca
3cb
, R = Me, 68%,  = 1:1
, R = Et, 70%,  = 1.2:1
O
O
R
3dd,
3de
3df
3dj
R = Ph, 75%,  = 3.3:1
, R = 2-MePh, 70%,  = 4:1
, R = 2-MeOPh, 55%,  = 2:1
, R = 4-FPh, 80%,  = 5.6:1
O
O
R
b
PMB
O
BnO
BnO
3ea
3eb
, R = Me, 65%,  = 1.5:1
, R = Et, 60%,  = 3.3:1
3cd
3ce
, R = Ph, 75%,  = 4.8:1
, R = 2-MePh,75%,  = 8:1
, R = 4-FPh, 76%,  = 6:1
O
R
O
tBu Si
O
R
3cj
O
O
tBu
c
PMB
O
3fd
O
Me
, R = Ph, 75% ,  only
O
tBu Si
c
3ed
3ee
, R = Ph, 82%,  only
, R = 2-MePh, 82%,  only
, R = 4-FPh, 80%,  only
3fe
, R = 2-MePh, 70% ,  only
c
3fh
, R = 4-MeOPh, 76% ,  only
O
tBu
3ej
c
3fi
3fj
, R = 4-MePh, 70% ,  only
c
3fa
, 77% ,  only
c
, R = 4-FPh, 88% ,  only
aReaction conditions unless otherwise noted: 1 (0.2 mmol), CuBr•SMe2 (0.2 mmol), RMgBr (0.4 mmol), ZnCl2
o
1
(0.3 mmol), Et2O (4 mL), N2 atmosphere, 30 C, 7-8 h. Isolated yield and the a/β ratios were determined by H
NMR. b55 oC, 10 h. c55 oC, 24 h.
According to the experimental results as well as the precedent literature,17 a plausible
reaction mechanism was proposed as shown in Figure 2. Firstly, organocopper reagent was
generated in situ through transmetallation with Grignard reagents. In the absence of any additive,
coordination of the organocopper reagent with the phosphorus atom of o-DPPB, the double bond
and the ring oxygen atom of glycal results in the formation of intermediate A with the
copper reagent disposed on the β-face of glycal. Subsequently, intramolecular syn-SN2’
substitution would take place to produce β-C-glycosides (a). On the other hand, in the presence of
ZnCl2 additive, Zn(II) competes with organic Cu(I) species to coordinate with the phosphorus
atom of o-DPPB and the ring oxygen atom of glycal, therefore forcing the approach of the in situ
generated organocopper reagent from the α-face. As a result, the anti-SN2’ substitution products
were obtained (b). As with the Pico group, the complexing of metal species to o-DPPB group will
also facilitate its departure. Thus, the carbocation species-involved substitution could not be
completely excluded.
ACS Paragon Plus Environment

Page 11 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
O
O
OPG
O
Ph2P
PPh2
OPG
R
CuRLn
(a)
O
O
O
O
-C-glycosides

1
GPO
A
CuLn + RMgBr
CuRLn
O
OPG
O
Zn2+
O
Ph2P
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(b)
O
PPh2
OPG
O
ZnCl2
R
O
GPO
-C-glycosides

O
B
CuRLn
1
Figure 2. Plausible mechanism for the divergent synthesis of C-glycosides.
With the reagent-controlled protocol for the divergent preparation of C-glycosides
established, the practicality as well as the flexibility of the protocol was then examined (Scheme
1). First of all, the coupling between 1a and 2d was scaled up to gram scale under the combined
effect of Cu(I)/ZnCl2, and, pleasantly, only a slight decrease in stereoselectivity and yield was
observed for 3ad (75% yield, α/β = 5 : 1, Scheme 1, a). Subsequently, the derivatization of α-3ad
was then investigated (a). Dihydroxylation of α-3ad with K2OsO4/NMO18 afforded diol
intermediate 5 as a single diastereomer (40%). Upon treatment with TFA at low temperature, 3ad
was converted to 6 smoothly (95%), which was then transformed either to 7 by hydrogenolysis
(82%) or to 9 via intermediate 8 through a sequence of acetylation and hydrogenolysis (95%, for 2
steps). In addition, dihydroxylation of 8 afforded 10 in a good yield of 76%. With the approval of
dapagliflozin as a drug for the treatment of type-II diabetes by FDA in 2014, the synthesis of
analogues thereof is drawing more and more interest from the synthetic chemists.19 Applying our
protocol, the C-glycosylation of 1120 with 1a proceeded without any event, furnishing 12 with a
α/β ratio of 5.4 : 1, from which the analogues of dapagliflozin could be easily accessed (b). Finally,
the synthesis of ethyl C-glycoside 13 was also studied (c). Thus, when the coupling between 1b
and 2b was carried out in the absence of additive, the desired β-ethyl-C-glycoside was formed
exclusively, which was then advanced to 13 via successive deisopropylidenation and acetylation
(51%, for 3 steps).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 44
1
2
3
O
O
Ph
O
Ph
O
NMO, K2OsO4
CuBr SMe2
O
O
PhMgBr
+
4
5
6
7
8
9
ZnCl2, Et2O
75%
PMB
AcO
O
THFH2O, rt
PMB
PMB
O
OH
O
2d
40%
O(o-DPPB)
5
OH
3ad 1.27g 
1a
(
= 5:1)
TFA, CH2Cl2
95%
-35 o
C
O
Ph
O
Ph
O
Ph
H2, Pd/C
HO
O
Ph
H , Pd/C
HO
AcO
2
Ac2O, Py
MeOH/EA, rt
82%
MeOH/EA
97%
98%
HO
HO
AcO
AcO
8
9
7
6
NMO, K2OsO4
THFH2O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
76%
Cl
OEt
(a)
Ph
O
O
HO
HO
AcO
OH
AcO
OH
10
OH
OH
Dapagliflozin
Cl
Cl
OEt
(b)
PMB
O
ZnCl2, CuBr SMe2
30 oC, Et2O, 55%
PMB
BrMg
O
O
O
+
O
O
O(o-DPPB)
1a
12  
(
5.4 1)

11
OEt
O
O
O
Et
AcO
1) CuBr SMe2, Et2O
(c)
EtMgBr
+
O
2) TFA, CH2Cl2
3) Ac2O, Py, 51%
(3 steps)
AcO
13
2b
O(o-DPPB)
(

only)
1d
Scheme 1. Investigation of the scalability and flexibility of the divergent synthetic protocol of
C-glycosylation.
Conclusions
In summary, a reagent-controlled protocol for the divergent synthesis of C-glycosides has been
devised. With o-DPPB as a directing group, the β-C-glycosidic linkages were constructed through
a syn-SN2’ substitution mechanism, while the α-C-glycosidic linkages were selectively forged by
silencing the directing effect of o-DPPB group so as to favor the anti-SN2’ substitution mechanism.
The turning off the directing effect of o-DPPB group was exquisitely achieved by the introduction
of ZnCl2 additive, thus being operationally easy and efficient. The protocol has been proven to be
scalable and flexible in the synthesis of C-glycosides, thus may find broad applications in the
future.
Experimental Section:
General Remarks
Commercial reagents were purchased and used without further purification, unless otherwise
stated. 1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded using CDCl3 or DMSO-d6
as solvents. Chemical shifts are reported in ppm downfield to tetramethylsilane. Coupling
constants are reported and expressed in Hz; splitting patterns are designated as s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), dd (double doublet), dt (double triplet), dq (double
quartet), br (broad). All reactions were carried out using freshly distilled and dried solvents. High
resolution mass spectra were performed on Thermo Fusion LUMOS mass spectrometer. Column
ACS Paragon Plus Environment

Page 13 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
chromatography was performed over silica gel (200-300 Mesh) using petroleum ether and ethyl
acetate as the eluent. The chemical structures of the new C-glycosides were determined by
1-dimmentional (1H and 13C) and 2-dimmentional (gCOSY, gHMQS, and NOE) NMR spectra.
4,6-O-4-Methoxybenzylidene-D-glucal (S2)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To a solution of D-(+)-glucal S121 (14.6 g, 0.10 mol) and 4-methoxybenzaldehyde dimethyl acetal
(29.5 mL, 0.15 mol) in dry DMF (150 mL), pyridinium p-toluenesulfonates (PPTS, 2.5 g, 0.01
mol) was added at 25 oC. The mixture was rotated on a Rotavapor for 4 h under reduced pressure
to remove the in situ generated methanol at the same temperature. The resulting mixture was
diluted with H2O (70 mL) and extracted with CH2Cl2 (3 × 250 mL). The combined organic layers
were washed successively with saturated aqueous NH4Cl, H2O, and brine, and were then dried
over anhydrous Na2SO4. Filtration was followed by concentration in vacuo to give the crude
product, which was further purified by flash chromatography on silica gel (EtOAc/PE = 1 : 2) to
afford S222 (17.2 g, 65%) as a white solid: [α]D23 = +45.8 (c 0.50, CHCl3); 1H NMR (400 MHz,
DMSO-d6) δ 7.38 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.37 (dd, J = 1.7, 6.1 Hz, 1H), 5.63
(s, 1H), 5.27 (d, J = 5.7 Hz, 1H), 4.68 (dd, J = 6.1, 1.9 Hz, 1H), 4.25 – 4.20 (m, 2H), 3.83 – 3.77
(m, 2H), 3.75 (s, 3H), 3.73 – 3.68 (m, 1H); 13C {1H} NMR (100 MHz, DMSO-d6) δ 159.6, 142.8,
130.0, 127.6, 113.3, 105.9, 100.6, 80.0, 68.5, 67.3, 65.0, 55.1; HRMS (ESI) m/z calcd for
C14H16O5Na [M + Na]+: 287.0890; found: 287.0887.
4,6-O-4-Methoxybenzylidene-D-galactal (S4)
To an ice-bath cooled solution of D-(+)-galactal S321 (1.46 g, 0.01 mol) and
4-methoxybenzaldehyde dimethyl acetal (2.95 mL, 0.015 mol) in freshly distilled CH3CN (8 mL),
PPTS (251 mg, 0.001 mol) was added at 0 oC. The reaction mixture was stirred at the same
temperature for 30 min, then was warmed up to room temperature and the stirring was continued
for another 24 h. The resulting mixture was diluted with H2O (10 mL) and extracted with CH2Cl2
(3 × 30 mL). The combined organic layers were washed successively with saturated aqueous
NH4Cl, H2O, and brine, and were then dried over anhydrous Na2SO4. Filtration was followed by
concentration in vacuo to give the crude product, which was further purified by flash
chromatography on silica gel (EtOAc/PE = 1 : 2) to afford S4 (1.05 g, 40%) as a white solid:
23
[α]D = -5.4 (c 2.28, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ 7.37 (d, J = 8.7 Hz, 2H), 6.93 (d,
J = 8.7 Hz, 2H), 6.75 (d, J = 6.2 Hz, 1H), 5.81 (s, 1H), 5.04 (dd, J = 6.2, 3.0 Hz, 1H), 4.95 (t, J =
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 44
1
2
3
4
5
6
7
8
9
5.6 Hz, 1H), 4.79 – 4.76 (m, 1H), 4.41 (d, J = 6.2 Hz, 1H), 3.86 (t, J = 6.6 Hz, 1H), 3.76 (s, 3H),
3.62 (t, J = 5.8 Hz, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 160.0, 148.2, 130.0, 128.4, 113.5,
101.3, 99.6, 76.3, 72.2, 69.1, 60.9, 55.2; HRMS (ESI) m/z calcd for C14H17O5 [M + H]+: 265.1070;
found: 265.1071.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for the preparation of 1
4-Dimethylaminopyridine (DMAP, 0.5 equiv) and dicyclohexylcarbodiimide (DCC, 1.3 equiv)
were added to a solution of ortho-diphenylphosphanylbenzoic acid (o-DPPBA, 1.1 equiv) in dry
DCM (2.0 mL) at 0 oC. After being stirred for 30 min at the same temperature, a solution of glycal
3-OH intermediate (10 mmol) in DCM (2.0 mL) was added. The resulting reaction mixture was
stirred for 10-12 h at 0 oC before EtOAc was added to dilute the reaction mixture. Filtration
through a pad of Celite and concentration under reduced pressure gave a residue, which was
further purified by silica gel column chromatography (petroleum ether/ethyl acetate) to afford
product 1.
3-O-(ortho-Diphenylphosphanyl)benzoyl-4,6-O-4-methoxybenzylidene-D-glucal (1a)
Following the general procedure described above, 4,6-O-4-methoxybenzylidene-glucal S2 (2.64 g,
23
10 mmol) was converted to 1a (5.08 g, 92%) as a white solid: [α]D = -143.1 (c 1.00, CHCl3); 1H
NMR (400 MHz, DMSO-d6) δ 7.97 (dt, J = 6.6, 3.8 Hz, 1H), 7.53 – 7.49 (m, 2H), 7.40 – 7.30 (m,
8H), 7.20 – 7.13 (m, 4H), 6.91 – 6.89 (m, 2H), 6.86 – 6.83 (m, 1H), 6.51 (dd, J = 6.0, 1.5 Hz, 1H),
5.54 (s, 1H), 5.50 (dt, J = 7.7, 1.8 Hz, 1H), 4.58 (dd, J = 6.1, 2.0 Hz, 1H), 4.28 (dd, J = 10.3, 5.0
Hz, 1H), 4.01 – 3.95 (m, 1H), 3.91 (dd, J = 10.3, 7.6 Hz, 1H), 3.78 (t, J = 10.1 Hz, 1H), 3.73 (s,
3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 166.1 (d, JC−P = 1.7 Hz), 159.6, 145.6, 139.2 (d, JC−P
= 27.3 Hz), 137.5 (d, JC−P = 10.4 Hz), 137.3 (d, JC−P = 12.1 Hz), 134.1 (d, JC−P = 20.7 Hz), 133.9,
133.4 (d, JC−P = 20.7 Hz), 132.4, 130.3 (d, JC−P = 2.8 Hz), 129.5, 128.8, 128.6 (d, JC−P = 7.0 Hz),
127.5, 113.4, 100.4, 99.9, 75.6, 69.5, 68.4, 67.1, 55.1; HRMS (ESI) m/z calcd for C33H30O6P [M +
H]+: 553.1775; found: 553.1774.
3-O-(ortho-Diphenylphosphanyl)benzoyl-4,6-O-(di-tert-butyl)silylene-D-glucal (1b)
Following the general procedure described above, 4,6-O-(di-tert-butyl)silylene-glucal S523 (2.86 g,
10 mmol) was converted to 1b (4.88 g, 85%) as a colorless oil: [α]D23 = -65.5 (c 1.00, CHCl3); 1H
NMR (400 MHz, DMSO-d6) δ 7.99 – 7.95 (m, 1H), 7.49 – 7.46 (m, 2H), 7.36 – 7.31 (m, 6H), 7.20
– 7.12 (m, 4H), 6.87 – 6.84 (m, 1H), 6.41 (dd, J = 6.0, 1.7 Hz, 1H), 5.43 (dt, J = 7.6, 1.9 Hz, 1H),
ACS Paragon Plus Environment

Page 15 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4.50 (dd, J = 6.1, 2.0 Hz, 1H), 4.16 – 4.09 (m, 2H), 3.96 – 3.87 (m, 2H), 0.97 (s, 9H), 0.89 (s, 9H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 166.0 (d, JC−P = 1.9 Hz), 145.1, 139.4 (d, JC−P = 27.5 Hz),
137.6 (d, JC−P = 12.7 Hz), 137.4 (d, JC−P = 12.1 Hz), 134.3 (d, JC−P = 20.3 Hz), 133.8, 133.5 (d,
JC−P = 20.9 Hz), 133.2 (d, JC−P = 20.7 Hz), 132.2, 130.0 (d, JC−P = 2.9 Hz), 128.7 (d, JC−P = 10.4
Hz), 128.6 (d, JC−P = 7.2 Hz), 128.5, 99.8, 73.2, 72.5, 72.2, 65.0, 27.1, 26.6, 22.2, 19.4; HRMS
(ESI) m/z calcd for C33H40O5PSi [M + H]+: 575.2377; found: 575.2371.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-O-(ortho-Diphenylphosphanyl)benzoyl-4,6-di-O-benzyl-D-glucal (1c)
Following the general procedure described above, 4,6-di-O-benzyl-glucal S624 (3.26 g, 10 mmol)
was successfully converted to 1c (5.77 g, 94%) as a colorless oil: [α]D23 = -39.9 (c 3.15, CHCl3);
1H NMR (400 MHz, DMSO-d6) δ 7.92 – 7.89 (m, 1H), 7.51 – 7.44 (m, 2H), 7.35 – 7.30 (m, 11H),
7.25 – 7.22 (m, 3H), 7.21 – 7.14 (m, 6H), 6.88 – 6.85 (m, 1H), 6.50 (dd, J = 6.1, 1.3 Hz, 1H), 5.39
– 5.37 (m, 1H), 4.58 (dd, J = 6.1, 3.1 Hz, 1H), 4.51 (t, J = 12.4 Hz, 4H), 4.18 – 4.14 (m, 1H), 3.82
(dd, J = 7.9, 5.9 Hz, 1H), 3.76 (dd, J = 10.9, 5.0 Hz, 1H), 3.67 (dd, J = 10.9, 3.0 Hz, 1H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 165.7 (d, JC−P = 2.1 Hz), 145.8, 139.6 (d, JC−P = 27.4 Hz), 138.0 (d,
JC−P = 10.1 Hz), 137.5 (d, JC−P = 6.4 Hz), 137.4 (d, JC−P = 6.3 Hz), 133.9, 133.7 (d, JC−P = 2.5 Hz),
133.6, 133.5 (d, JC−P = 2.9 Hz), 133.3, 132.4, 130.3, 128.8 (3C), 128.7 (2C), 128.6 (2C), 128.2 (d,
JC−P = 9.2 Hz), 127.7, 127.6, 127.5 (d, JC−P = 3.9 Hz), 98.2, 75.9, 72.9, 72.5, 72.4, 70.4, 67.7;
HRMS (ESI) m/z calcd for C39H39O5PN [M + NH4]+: 632.2560; found: 632.2558.
3-O-(ortho-Diphenylphosphanyl)benzoyl-4,6-O-isopropylidene-D-glucal (1d)
Following the general procedure described above, 4,6-O-isopropylidene-glucal S725 (1.86 g, 10
mmol) was converted to 1d (4.03 g, 85%) as a colorless oil: [α]D23 = -104.8 (c 1.00, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 8.00 – 7.97 (m, 1H), 7.38 – 7.32 (m, 2H), 7.31 – 7.19 (m, 10H), 6.90 –
6.87 (m, 1H), 6.22 (dd, J = 6.1, 1.5 Hz, 1H), 5.43 (dt, J = 7.7, 1.8 Hz, 1H), 4.56 (dd, J = 6.1, 2.0
Hz, 1H), 3.98 – 3.89 (m, 2H), 3.80 – 3.69 (m, 2H), 1.42 (s, 3H), 1.34 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 166.8 (d, JC−P = 2.2 Hz), 145.3, 140.6 (d, JC−P = 27.2 Hz), 138.2 (d, JC−P = 11.4
Hz), 138.0 (d, JC−P = 11.5 Hz), 134.6 (d, JC−P = 19.4 Hz), 134.5, 134.3, 134.1 (d, JC−P = 2.9 Hz),
133.9, 132.1, 130.8 (d, JC−P = 2.9 Hz), 128.7, 128.6 (d, JC−P = 7.3 Hz), 128.3, 101.0, 99.9, 70.5,
69.9, 69.8, 61.8, 29.0, 19.2; HRMS (ESI) m/z calcd for C28H27O5PNa [M + Na]+: 497.1488; found:
497.1491.
3-O-(ortho-Diphenylphosphanyl)benzoyl-4,6-O-4-methoxybenzylidene-D-galactal (1e)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 44
1
2
3
4
5
6
7
8
9
Following the general procedure described above, S4 (2.64 g, 10 mmol) was converted to 1e (2.21
g, 40%) as a white solid: [α]D23 = +141.4 (c 1.00, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ 7.96
– 7.93 (m, 1H), 7.50 – 7.47 (m, 2H), 7.38 – 7.29 (m, 8H), 7.20 – 7.15 (m, 4H), 6.91 – 6.86 (m,
3H), 6.53 (dd, J = 6.4, 2.1 Hz, 1H), 5.58 (s, 1H), 5.53 (dt, J = 4.7, 2.1 Hz, 1H), 4.58 (dt, J = 6.4,
1.8 Hz, 1H), 4.48 – 4.47 (m, 1H), 4.15 (dd, J = 12.3, 1.8 Hz, 1H), 4.08 – 4.03 (m, 2H), 3.73 (s,
3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 165.6 (d, JC−P = 1.6 Hz), 159.4, 145.2, 139.6 (d, JC−P
= 27.3 Hz), 137.5 (d, JC−P = 6.1 Hz), 137.4 (d, JC−P = 6.4 Hz), 134.0 (d, JC−P = 19.8 Hz), 133.7,
133.5 (d, JC−P = 3.0 Hz), 133.3 (d, JC−P = 2.8 Hz), 132.3, 130.5, 130.3 (d, JC−P = 2.9 Hz), 128.8 (d,
JC−P = 2.3 Hz), 128.7, 128.6 (2C), 127.3, 113.3, 99.5, 97.3, 68.9, 68.4, 67.6, 66.4, 55.1; HRMS
(ESI) m/z calcd for C33H30O6P [M + H]+: 553.1774; found: 553.1770.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-O-(ortho-Diphenylphosphanyl)benzoyl-4,6-O-(di-tert-butyl)silylene-D-galactal (1f)
Following the general procedure described above, 4,6-O-(di-tert-butyl)silylene-galactal S823 (2.86
g, 10 mmol) was converted to 1f (4.94 g, 86%) as a white solid: [α]D23 = +147.0 (c 1.00, CHCl3);
1H NMR (400 MHz, DMSO-d6) δ 8.04 – 8.00 (m, 1H), 7.51 – 7.48 (m, 2H), 7.38 – 7.34 (m, 6H),
7.19 – 7.12 (m, 4H), 6.87 – 6.84 (m, 1H), 6.52 (dd, J = 6.4, 1.9 Hz, 1H), 5.30 (dt, J = 4.4, 2.0 Hz,
1H), 4.74 (dd, J = 5.4, 1.8 Hz, 1H), 4.64 (dt, J = 6.4, 1.8 Hz, 1H), 4.19 (dd, J = 12.7, 1.9 Hz, 1H),
4.12 (dd, J = 12.7, 1.8 Hz, 1H), 4.05 (s, 1H), 0.97 (s, 9H), 0.86 (s, 9H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 165.6, 145.7, 139.6 (d, JC−P = 27.4 Hz), 137.7 (d, JC−P = 12.9 Hz), 137.5 (d, JC−P
=
11.1 Hz), 134.3 (d, JC−P = 20.2 Hz), 133.8, 133.6 (d, JC−P = 20.8 Hz), 133.1 (d, JC−P = 20.4 Hz),
132.3, 130.3 (d, JC−P = 3.0 Hz), 128.7 (d, JC−P = 12.4 Hz), 128.6 (2C), 128.5, 98.2, 72.5, 68.0, 66.8,
64.5, 27.3, 26.9, 22.7, 20.5; HRMS (ESI) m/z calcd for C33H40O5PSi [M + H]+: 575.2377; found:
575.2370.
3-O-(ortho-Diphenylphosphinyl)benzoyl-4,6-O-4-methoxybenzylidene-D-glucal (S9)
Aqueous H2O2 (30%, 171.3 mg, 5 mmol) was added to a magnetically stirred solution of 1a (552.5
mg, 1 mmol) in THF (10 mL) at room temperature, the mixture was stirred at the same
temperature for another 2 h before water (10 mL) was added to dilute the reaction mixture. The
resulting solution was extracted with EtOAc (3 × 20 mL). The combined organic layers were
washed with H2O and brine, and then dried over anhydrous Na2SO4. Filtration and concentration
in vacuo gave a residue, which was purified by flash chromatography on silica gel (EtOAc/PE = 1 :
1) to afford product S9 (500 mg, 88%) as a white solid: [α]D23 = -165.7 (c 1.00, CHCl3); 1H NMR
ACS Paragon Plus Environment

Page 17 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(400 MHz, DMSO-d6) δ 7.80 – 7.77 (m, 1H), 7.73 – 7.69 (m, 1H), 7.67 – 7.62 (m, 2H), 7.61 –
7.48 (m, 9H), 7.39 – 7.34 (m, 1H), 7.32 – 7.30 (m, 2H), 6.93 – 6.89 (m, 2H), 6.46 (dd, J = 6.1, 1.6
Hz, 1H), 5.45 (s, 1H), 5.36 (dt, J = 8.0, 1.8 Hz, 1H), 4.73 (dd, J = 6.2, 2.0 Hz, 1H), 4.25 (dd, J =
10.3, 5.2 Hz, 1H), 3.95 – 3.89 (m, 1H), 3.74 – 3.69 (m, 4H), 3.53 (dd, J = 10.3, 8.0 Hz, 1H);
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13C{1H} NMR (100 MHz, DMSO-d6) δ 166.9 (d, JC−P = 3.1 Hz), 159.6, 145.0, 135.8 (d, JC−P
=
6.0 Hz), 133.9 (d, JC−P = 28.1 Hz), 133.9, 132.8 (d, JC−P = 18.1 Hz), 132.2, 131.8, 131.4 (d, JC−P
=
9.6 Hz), 131.4 (d, JC−P = 9.8 Hz), 131.2, 131.1 (d, JC−P = 11.5 Hz), 130.0 (d, JC−P = 8.4 Hz), 129.5,
128.6 (d, JC−P = 12.0 Hz), 128.5 (d, JC−P = 12.1 Hz), 127.6, 113.4, 100.5, 99.8, 75.3, 69.7, 68.2,
67.2, 55.1; HRMS (ESI) m/z calcd for C33H30O7P [M + H]+: 569.1724; found: 569.1721.
General procedure for the synthesis of C-glycosides 3β
CuBr•SMe2 (0.2 mmol) was added to a solution of 1 (0.2 mmol) in dry Et2O (4 mL), and the
mixture was stirred for 30 min at room temperature before RMgBr 2 (0.4 mmol) was added at 0
°C. The mixture was allowed to warm to 30 °C and was stirred for another 7-8 h at the same
temperature, at which time TLC showed that all starting material 1 was consumed. Then the
reaction was quenched by adding aqueous saturated NH4Cl (2.5 mL), which was followed by the
addition of EtOAc (10 mL) and NH3•H2O (12.5%, 2 mL). The resulting mixture was extracted
with EtOAc (3 × 10 mL). The combined organic phases were washed with water then brine, and
were then dried over anhydrous Na2SO4. Filtration and concentration in vacuo gave a residue,
which was purified by chromatography on silica gel (EtOAc/PE) to afford 3β.
General procedure for the preparation of C-glycosides 3α
To an ice-bath cooled suspension of CuBr•SMe2 (0.2 mmol) and ZnCl2 (1 M in Et2O, 0.3 mmol) in
dry Et2O (2 mL) was added a solution of RMgBr 2 (0.4 mmol) slowly. The mixture was stirred at
the same temperature for 60 min before the addition of a solution of ester 1 (0.2 mmol) in Et2O (2
mL). The resulting mixture was allowed to warm to 30 oC or 55 oC and the stirring was continued
for another 7-24 h, at which time TLC showed that all starting material 1 was consumed. Saturated
aqueous solution of NH4Cl (2.5 mL) and NH3•H2O (12.5%, 2 mL) were added successively after
the reaction mixture was diluted with EtOAc (10 mL). The resulting mixture was extracted with
EtOAc (3 × 10 mL). The combined organic extracts were washed with saturated aqueous NH4Cl,
H2O, and brine successively, and were then dried over anhydrous Na2SO4. Filtration was followed
by concentration in vacuo afforded the crude product, which was further purified by flash
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 44
1
2
3
4
5
6
7
8
9
chromatography on silica gel (using EtOAc/PE) to afford 3α as predominant products.
Methyl 4,6-O-4-methoxybenzylidene-2,3-dideoxy-β-D-C-erythro-hex-2-enopyranoside (3aa)
Following the general procedure for the synthesis of β-C-glycosides, the coupling between 1a and
2a afforded 3aa (30.6 mg, 59%) as a white solid after silica gel column chromatography
(petroleum ether/ethyl acetate = 15 : 1): [α]D23 = +26.3 (c 2.43, CHCl3); 1H NMR (400 MHz,
DMSO-d6) δ 7.34 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.84 (d, J = 9.7 Hz, 1H), 5.75 (dt,
J = 10.2, 2.0 Hz, 1H), 5.61 (s, 1H), 4.40 – 4.37 (m, 1H), 4.19 – 4.14 (m, 2H), 3.74 – 3.70 (m, 4H),
3.48 – 3.42 (m, 1H), 1.17 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 159.5,
132.9, 130.2, 127.6, 125.3, 113.3, 100.9, 74.4, 71.6, 70.8, 68.5, 55.1, 20.7; HRMS (ESI) m/z calcd
for C15H19O4 [M + H]+: 263.1278; found: 263.1275.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl 4,6-O-4-methoxybenzylidene-2,3-dideoxy-β-D-C-erythro-hex-2-enopyranoside (3ab)
Following the general procedure for the synthesis of β-C-glycosides, the coupling between 1a and
2b provided 3ab (29.8 mg, 54%) as a white solid after silica gel column chromatography
(petroleum ether/ethyl acetate = 15 : 1): [α]D23 = +4.5 (c 0.55, CHCl3); 1H NMR (400 MHz,
DMSO-d6) δ 7.34 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.89 (d, J = 10.3 Hz, 1H), 5.76 (dt,
J = 10.3, 2.1 Hz, 1H), 5.62 (s, 1H), 4.27 – 4.22 (m, 1H), 4.18 – 4.14 (m, 2H), 3.75 (s, 3H), 3.72 (d,
J = 10.2 Hz, 1H), 3.46 – 3.40 (m, 1H), 1.63 – 1.42 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 159.5, 131.4, 130.2, 127.6, 126.2, 113.3, 100.8, 76.2, 74.5, 70.6,
68.5, 55.1, 27.4, 9.0; HRMS (ESI) m/z calcd for C16H21O4 [M + H]+: 277.1434; found: 277.1432.
Propyl 4,6-O-4-methoxybenzylidene-2,3-dideoxy-β-D-C-erythro-hex-2-enopyranoside (3ac)
Following the general procedure for the synthesis of β-C-glycosides, the coupling between 1a and
2c furnished 3ac (32.0 mg, 55%) as a white solid after silica gel column chromatography
(petroleum ether/ethyl acetate = 15 : 1): [α]D23 = +15.6 (c 0.50, CHCl3); 1H NMR (400 MHz,
DMSO-d6) δ 7.34 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 5.87 (d, J = 10.4 Hz, 1H), 5.76 (dt,
J = 10.3, 2.0 Hz, 1H), 5.61 (s, 1H), 4.29 – 4.25 (m, 1H), 4.16 (dd, J = 10.1, 4.3 Hz, 2H), 3.75 (s,
3H), 3.71 (d, J = 10.3 Hz, 1H), 3.46 – 3.40 (m, 1H), 1.55 – 1.43 (m, 2H), 1.41 – 1.33 (m, 2H),
0.88 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 159.5, 131.7, 130.2, 127.6, 125.9,
113.3, 100.8, 75.0, 74.5, 70.7, 68.5, 55.1, 36.6, 17.6, 13.9; HRMS (ESI) m/z calcd for C17H23O4
[M + H]+: 291.1591; found: 291.1588.
Phenyl 4,6-O-4-methoxybenzylidene-2,3-dideoxy-α/β-D-C-erythro-hex-2-enopyranoside (3ad)
ACS Paragon Plus Environment

Page 19 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Following the general procedure for the synthesis of β-C-glycosides, the coupling between 1a and
2d provided 3ad (26.0 mg, 40%) as a mixture of α/β isomers with the β-3ad being the major
product (α : β = 4:5). An aliquot of pure β-isomer was obtained for detailed characterization:
[α]D23 = +19.7 (c 1.70, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ 7.40 – 7.30 (m, 7H), 6.93 (d, J
= 8.7 Hz, 2H), 6.00 (d, J = 9.6 Hz, 1H), 5.83 (dt, J = 10.4, 2.1 Hz, 1H), 5.69 (s, 1H), 5.37 (q, J =
2.5 Hz, 1H), 4.40 – 4.36 (m, 1H), 4.21 (dd, J = 10.0, 4.6 Hz, 1H), 3.81 (t, J = 10.2 Hz, 1H), 3.76 (s,
3H), 3.70 – 3.64 (m, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 159.5, 140.1, 131.2, 130.1,
128.4, 128.0, 127.6, 127.2, 125.9, 113.4, 100.9, 77.5, 74.1, 71.2, 68.4, 55.2; HRMS (ESI) m/z
calcd for C20H21O4 [M + H]+: 325.1434; found: 325.1437.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 4,6-O-(di-tert-butyl)silylene-2,3-dideoxy-β-D-C-erythro-hex-2-enopyranoside (3ba)
Following the general procedure for the synthesis of β-C-glycosides, the coupling between 1b and
2a provided 3ba (28.4 mg, 50%) as a colorless oil after silica gel column chromatography
(petroleum ether/ethyl acetate = 100 : 1): [α]D23 = +6.1 (c 0.50, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 5.81 (dt, J = 10.3, 1.9 Hz, 1H), 5.60 (dt, J = 10.4, 1.8 Hz, 1H), 4.43 – 4.39 (m, 1H), 4.34
– 4.28 (m, 1H), 4.18 (dd, J = 10.2, 5.3 Hz, 1H), 3.88 (t, J = 10.2 Hz, 1H), 3.54 – 3.48 (m, 1H),
1.20 (d, J = 6.7 Hz, 3H), 1.05 (s, 9H), 0.99 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 131.1,
129.2, 74.9, 71.8, 70.4, 67.4, 27.7, 27.3, 22.8, 21.2, 20.2; HRMS (ESI) m/z calcd for C15H29O3Si
[M + H]+: 285.1881; found: 285.1885.
Ethyl 4,6-O-(di-tert-butyl)silylene-2,3-dideoxy-β-D-C-erythro-hex-2-enopyranoside (3bb)
Following the general procedure for the synthesis of β-C-glycosides, the coupling between 1b and
2b provided 3bb (28.6 mg, 48.0%) as a colorless oil after silica gel column chromatography
(petroleum ether/ethyl acetate =100 :1): [α]D23 = +24.7 (c 0.20, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 5.84 (dt, J = 10.4, 1.9 Hz, 1H), 5.62 (dt, J = 10.4, 1.9 Hz, 1H), 4.40 – 4.36 (m, 1H), 4.19
– 4.12 (m, 2H), 3.87 (t, J = 10.2 Hz, 1H), 3.52 – 3.46 (m, 1H), 1.57 – 1.47 (m, 2H), 1.05 (s, 9H),
0.99 (s, 9H), 0.91 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 130.0, 129.6, 76.6,
74.8, 70.6, 67.5, 28.3, 27.7, 27.3, 22.8, 20.2, 9.2; HRMS (ESI) m/z calcd for C16H30O3SiNa [M +
Na]+: 321.1856; found: 321.1859.
Propyl 4,6-O-(di-tert-butyl)silylene-2,3-dideoxy-β-D-C-erythro-hex-2-enopyranoside (3bc)
Following the general procedure for the synthesis of β-C-glycosides, the coupling between 1b and
2c provided 3bc (34.3 mg, 55%) as a white solid after silica gel column chromatography
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 44
1
2
3
4
5
6
7
8
9
(petroleum ether/ethyl acetate = 100 : 1): [α]D23 = +27.6 (c 1.00, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 5.82 (dt, J = 10.5, 2.0 Hz, 1H), 5.61 (dt, J = 10.4, 1.9 Hz, 1H), 4.40 – 4.36 (m, 1H), 4.21
– 4.15 (m, 2H), 3.86 (t, J = 10.2 Hz, 1H), 3.51 – 3.45 (m, 1H), 1.50 – 1.44 (m, 2H), 1.42 – 1.31 (m,
2H), 1.05 (s, 9H), 0.98 (s, 9H), 0.90 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
130.1, 129.7, 75.4, 74.8, 70.6, 67.5, 37.6, 27.7, 27.3, 22.8, 20.2, 18.2, 14.2; HRMS (ESI) m/z
calcd for C17H32O3SiNa [M + Na]+: 335.2013; found: 335.2012.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Phenyl 4,6-O-(di-tert-butyl)silylene-2,3-dideoxy-α/β-D-C-erythro-hex-2-enopyranoside (3bd)
Following the general procedure for the synthesis of β-C-glycosides, the coupling between 1b and
2d provided 3bd (29.8 mg, 43%) as a mixture of α/β epimers with the β-isomer as the major
23
product (α:β = 1 : 2). An aliquot of pure β-3bd was obtained for detailed characterization: [α]D
=
+2.4 (c 2.03, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.29 (m, 5H), 5.97 (dt, J = 10.3, 2.0
Hz, 1H), 5.74 (dt, J = 10.3, 1.9 Hz, 1H), 5.23 (d, J = 2.3 Hz, 1H), 4.59 – 4.56 (m, 1H), 4.22 (dd, J
= 10.0, 5.0 Hz, 1H), 3.95 (t, J = 10.2 Hz, 1H), 3.76 – 3.70 (m, 1H), 1.08 (s, 9H), 1.02 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3) δ 140.3, 130.0, 129.5, 128.8, 128.4, 127.5, 78.4, 75.5, 70.3,
67.4, 27.7, 27.3, 22.9, 20.3; HRMS (ESI) m/z calcd for C20H31O3Si [M + H]+: 347.2037; found:
347.2038.
Methyl 4,6-di-O-benzyl-2,3-dideoxy-β-D-C-erythro-hex-2-enopyranoside (3ca)
Following the general procedure for the synthesis of β-C-glycosides, the coupling between 1c and
2a provided 3ca (29.7 mg, 46%) as a colorless oil after silica gel column chromatography
(petroleum ether/ethyl acetate = 20 : 1): [α]D23 = +28.4 (c 0.40, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.36 – 7.20 (m, 10H), 5.86 (dt, J = 10.2, 2.1 Hz, 1H), 5.73 (dt, J = 10.3, 1.5 Hz, 1H),
4.63 – 4.54 (m, 3H), 4.42 (d, J = 11.4 Hz, 1H), 4.30 – 4.23 (m, 1H), 4.01 – 3.98 (m, 1H), 3.75 –
3.70 (m, 1H), 3.64 – 3.60 (m, 2H), 1.23 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
138.5, 138.3, 133.4, 128.5 (2C), 128.1, 127.9, 127.7, 125.5, 77.3, 73.6, 71.2, 70.9, 67.0, 21.4;
HRMS (ESI) m/z calcd for C21H25O3 [M + H]+: 325.1798; found: 325.1796.
Ethyl 4,6-di-O-benzyl-2,3-dideoxy-β-D-C-erythro-hex-2-enopyranoside (3cb)
Following the general procedure for the synthesis of β-C-glycosides, the coupling between 1c and
2b furnished 3cb (29.8 mg, 44%) as a colorless oil after silica gel column chromatography
(petroleum ether/ethyl acetate = 20 : 1): [α]D23 = +33.7 (c 0.55, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.38 – 7.24 (m, 10H), 5.91 (dt, J = 10.3, 2.1 Hz, 1H), 5.77 (dt, J = 10.4, 1.5 Hz, 1H),
ACS Paragon Plus Environment

Page 21 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4.66 – 4.58 (m, 3H), 4.46 (d, J = 11.5 Hz, 1H), 4.10 – 4.06 (m, 1H), 4.01 – 3.98 (m, 1H), 3.78 –
3.73 (m, 1H), 3.67 – 3.60 (m, 2H), 1.62 – 1.58 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 138.6, 138.3, 131.9, 128.5, 128.4, 128.0 (2C), 127.8, 127.6, 126.2, 77.4, 76.0,
73.5, 71.2, 71.1, 70.0, 28.4, 9.4; HRMS (ESI) m/z calcd for C22H26O3Na [M + Na]+: 361.1774;
found: 361.1772.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Phenyl 4,6-di-O-benzyl-2,3-dideoxy-α/β-D-C-erythro-hex-2-enopyranoside (3cd)
Following the general procedure for the synthesis of β-C-glycosides, the coupling between 1c and
2d provided 3cd (30.9 mg, 40.0%) as a mixture of α/β diastereomers with the β-isomer being the
major product (α/β = 1 : 2.5). The pure β-3cd was obtained as a colorless oil after silica gel
column chromatography (petroleum ether/ethyl acetate = 20 : 1) for detailed characterization:
[α]D23 = +86.0 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.25 (m, 15H), 5.99 (dt, J =
10.3, 2.1 Hz, 1H), 5.85 (dt, J = 10.3, 1.7 Hz, 1H), 5.18 (q, J = 2.3 Hz, 1H), 4.67 – 4.50 (m, 4H),
4.17 – 4.14 (m, 1H), 3.85 – 3.79 (m, 2H), 3.73 (dd, J = 11.0, 5.6 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 140.9, 138.6, 138.2, 131.8, 128.6 (2C), 128.4, 128.1 (2C), 128.0, 127.9, 127.6,
127.3, 126.2, 78.0, 77.6, 73.6, 71.4, 70.7, 70.1; HRMS (ESI) m/z calcd for C26H27O3 [M + H]+:
387.1955; found: 387.1955.
Phenyl 4,6-O-isopropylidene-2,3-dideoxy-α/β-D-C-erythro-hex-2-enopyranoside (3dd)
Following the general procedure for the synthesis of β-C-glycosides, the coupling between 1d and
2d afforded 3dd (22.2 mg, 45%) as a mixture of α/β diastereomers with the β-3dd as the
predominating product (α/β = 3 : 5, determined by 1H NMR).
Methyl 4,6-O-4-methoxybenzylidene-2,3-dideoxy-β-D-C-threo-hex-2-enopyranoside (3ea)
Following the general procedure for the synthesis of β-C-glycosides, the coupling between 1e and
2a afforded 3ea (22.0 mg, 42%) as a colorless oil after silica gel column chromatography
(petroleum ether/ethyl acetate = 12 : 1): [α]D23 = -7.5 (c 1.00, CHCl3); 1H NMR (400 MHz,
DMSO-d6) δ 7.32 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.96 (d, J = 10.8 Hz, 1H), 5.87 –
5.83 (m, 1H), 5.55 (s, 1H), 4.24 – 4.20 (m, 2H), 4.15 (dd, J = 12.7, 2.5 Hz, 1H), 4.09 (dd, J = 12.8,
1.3 Hz, 1H), 3.74 (s, 3H), 3.38 (s, 1H), 1.21 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 159.3, 136.5, 131.0, 127.4, 122.9, 113.2, 99.4, 70.5, 69.6, 68.4, 67.8, 55.1, 20.6;
HRMS (ESI) m/z calcd for C15H19O4 [M + H]+: 263.1278; found: 263.1277.
Ethyl 4,6-O-4-methoxybenzylidene-2,3-dideoxy-β-D-C-threo-hex-2-enopyranoside (3eb)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 44
1
2
3
4
5
6
7
8
9
Following the general procedure for the synthesis of β-C-glycosides, the coupling between 1e and
2b gave 3eb (22.1 mg, 40%) as a colorless oil after silica gel column chromatography (petroleum
ether/ethyl acetate = 12 : 1): [α]D23 = -2.7 (c 1.57, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ 7.32
(d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 5.97 (d, J = 10.7 Hz, 1H), 5.91 – 5.87 (m, 1H), 5.55
(s, 1H), 4.24 – 4.22 (m, 1H), 4.15 (dd, J = 12.7, 2.4 Hz, 1H), 4.11 – 4.02 (m, 2H), 3.74 (s, 3H),
3.45 (s, 1H), 1.61 – 1.50 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6)
δ 159.4, 135.2, 131.1, 127.4, 123.6, 113.2, 99.4, 75.1, 69.6, 68.1, 68.0, 55.1, 27.2, 9.2; HRMS
(ESI) m/z calcd for C16H21O4 [M + H]+: 277.1434; found: 277.1435.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 4,6-O-4-methoxybenzylidene-2,3-dideoxy-α/β-D-C-erythro-hex-2-enopyranoside (3aa)
Following the general procedure for the preparation of α-C-glycosides, the coupling between 1a
and 2a under the effect of CuBr•SMe2/ZnCl2 provided 3aa (46.1 mg, 88%) as a mixture of α/β
diastereomers with α-3aa as the predominant product (α/β = 3.2:1). The pure α-3aa was obtained
as a white solid for detailed characterization: [α]D23 = +19.0 (c 1.63, CHCl3); 1H NMR (400 MHz,
DMSO-d6) δ 7.35 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.87 (d, J = 10.2 Hz, 1H), 5.77 (dt,
J = 10.4, 2.5 Hz, 1H), 5.61 (s, 1H), 4.44 – 4.38 (m, 1H), 4.14 – 4.09 (m, 2H), 3.75 (s, 3H), 3.70 (t,
J = 10.2 Hz, 1H), 3.48 – 3.42 (m, 1H), 1.25 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 159.5, 132.4, 130.2, 127.6, 125.7, 113.4, 100.9, 74.4, 69.7, 68.8, 64.8, 55.1, 19.0;
HRMS (ESI) m/z calcd for C15H19O4 [M + H]+: 263.1278; found: 263.1275.
Ethyl 4,6-O-4-methoxybenzylidene-2,3-dideoxy-α/β-D-C-erythro-hex-2-enopyranoside (3ab)
Following the general procedure for the preparation of α-C-glycosides, the coupling between 1a
and 2b under the effect of CuBr•SMe2/ZnCl2 provided 3ab (41.4 mg, 75%) as a mixture of α/β
diastereomers (α/β = 2 : 1) with the α-isomer being the predominant product. The pure α-3ab was
obtained as a white solid for detailed characterization: [α]D23 = +4.0 (c 1.83, CHCl3); 1H NMR
(400 MHz, DMSO-d6) δ 7.34 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.90 (d, J = 10.5 Hz,
1H), 5.82 (dt, J = 10.4, 2.3 Hz, 1H), 5.61 (s, 1H), 4.15 – 4.07 (m, 3H), 3.74 (s, 3H), 3.70 (d, J =
10.2 Hz, 1H), 3.42 – 3.38 (m, 1H), 1.68 – 1.50 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13C{1H} NMR
(100 MHz, DMSO-d6) δ 159.5, 131.1, 130.2, 127.6, 126.1, 113.4, 100.9, 74.9, 74.6, 68.8, 65.2,
55.1, 25.9, 10.8; HRMS (ESI) m/z calcd for C16H21O4 [M + H]+: 277.1434; found: 277.1429.
Propyl 4,6-O-4-methoxybenzylidene-2,3-dideoxy-α/β-D-C-erythro-hex-2-enopyranoside (3ac)
Following the general procedure for the synthesis of α-C-glycosides, the coupling between 1a and
ACS Paragon Plus Environment

Page 23 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2c under the effect of CuBr•SMe2/ZnCl2 provided 3ac (44.1 mg, 76.0%) as a mixture of α/β
diastereomers with the α-isomer being the predominant product (α/β = 2.5 : 1). The pure α-3ac
was obtained as a white solid for detailed characterization: [α]D23 = +3.3 (c 1.00, CHCl3); 1H NMR
(400 MHz, DMSO-d6) δ 7.34 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 5.88 (d, J = 10.0 Hz,
1H), 5.80 (dt, J = 10.5, 2.4 Hz, 1H), 5.61 (s, 1H), 4.20 (d, J = 7.9 Hz, 1H), 4.14 – 4.10 (m, 2H),
3.75 (s, 3H), 3.70 (t, J = 10.2 Hz, 1H), 3.43 – 3.37 (m, 1H), 1.65 (q, J = 9.2 Hz, 1H), 1.48 – 1.41
(m, 2H), 1.39 – 1.32 (m, 1H), 0.91 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ
159.5, 131.3, 130.2, 127.6, 125.9, 113.3, 100.8, 74.6, 73.2, 68.8, 65.1, 55.1, 34.7, 19.0, 13.8;
HRMS (ESI) m/z calcd for C17H23O4 [M + H]+: 291.1591; found: 291.1590.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Phenyl 4,6-O-4-methoxybenzylidene-2,3-dideoxy-α/β-D-C-erythro-hex-2-enopyranoside (3ad)
Following the general procedure for the synthesis of α-C-glycosides, the coupling between 1a and
2d under the effect of CuBr•SMe2/ZnCl2 provided 3ad (58.3 mg, 90%) as a mixture of α/β
diastereomers with the α-isomer being the predominant product (α/β = 5.2:1). The pure α-3ad was
obtained as a white solid for detailed characterization: [α]D23 = +72.5 (c 1.00, CHCl3); 1H NMR
(400 MHz, DMSO-d6) δ 7.41 (d, J = 4.3 Hz, 4H), 7.36 – 7.32 (m, 3H), 6.90 (d, J = 8.7 Hz, 2H),
6.13 (t, J = 12.1, 2H), 5.65 (s, 1H), 5.38 (s, 1H), 4.28 (dt, J = 8.4, 1.9 Hz, 1H), 4.10 (dd, J = 10.2,
4.6 Hz, 1H), 3.77 (d, J = 10.3 Hz, 1H), 3.74 (s, 3H), 3.42 – 3.38 (m, 1H); 13C{1H} NMR (100
MHz, DMSO-d6) δ 159.5, 139.7, 130.1, 129.6, 128.5, 127.8, 127.6, 127.2 (2C), 113.4, 101.0, 74.3,
74.1, 68.4, 65.3, 55.1; HRMS (ESI) m/z calcd for C20H21O4 [M + H]+: 325.1434; found: 325.1437.
Phenyl 4,6-O-4-methoxybenzylidene-2,3-dideoxy-α/β-D-erythro-hex-2-eno-C-pyranoside
(3ad)---in gram scale synthesis
Following the general procedure for the synthesis of α-C-glycosides, the coupling between 1a
(2.76 g, 5.0 mmol) and 2d (3M in ether, 3.34 mL, 10.0 mmol) under the effect of CuBr•SMe2 (1.0
g, 5.0 mmol)/ZnCl2 (1M in ether, 7.5 mL, 7.5 mmol) provided 3ad (1.27 g, 75%) as a mixture of
α/β diastereomers with the α-isomer being the predominant product (α/β = 5:1).
ortho-Methylphenyl
4,6-O-4-methoxybenzylidene-2,3-dideoxy-α/β-D-erythro-hex-2-eno-C-pyranoside (3ae)
Following the general procedure for the preparation of α-C-glycosides, the coupling between 1a
and 2e under the effect of CuBr•SMe2/ZnCl2 provided 3ae (58.2 mg, 86%) as a mixture of α/β
diastereomers with the α-isomer being the predominant product (α/β = 4:1 and the value was
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 44
1
2
3
4
determined by 1H NMR). The α/β isomers of 3ae were inseparable by silica gel column
5
6
23
chromatography (petroleum ether/ethyl acetate = 15 : 1), thus were determined as a mixture: [α]D
7
8
9
= +35.3 (c 1.68, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ 7.37 (dd, J = 13.8, 8.4 Hz, 2H), 7.29 –
7.19 (m, 4H), 6.92 (t, J = 9.1 Hz, 2H), 6.21 (d, J = 10.4 Hz, 0.8H), 6.03 (dt, J = 10.7, 2.9 Hz, 1H),
5.83 (d, J = 10.4 Hz, 0.2H), 5.69 (s, 0.2H), 5.64 (s, 0.8H), 5.57 (d, J = 2.7 Hz, 0.2H), 5.55 (d, J =
2.7 Hz, 0.8H), 4.40 (d, J = 8.2 Hz, 0.2H), 4.28 (d, J = 8.2 Hz, 0.8H), 4.21 (dd, J = 10.2, 4.7 Hz,
0.2H), 3.95 (dd, J = 10.2, 4.7 Hz, 0.8H), 3.81 (d, J = 10.2 Hz, 0.2H), 3.76 (s, 0.6H), 3.74 (s, 2.4H),
3.71 (d, J = 10.2 Hz, 0.8H), 3.35 (s, 0.8H), 3.32 (d, J = 5.2 Hz, 0.2H), 2.40 (s, 2.4H), 2.35 (s,
0.6H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 159.5, 137.8, 137.4, 136.9, 135.8, 130.7, 130.4,
130.1 (2C), 129.5, 128.3, 127.9 (2C), 127.7, 127.6, 127.4, 126.0, 125.9, 125.3, 113.4, 113.3, 100.9,
75.3, 74.6, 74.2, 71.6, 71.3, 68.6, 68.4, 64.7, 55.1, 18.7; HRMS (ESI) m/z calcd for C21H22O4 Na
[M + Na]+: 361.1410; found: 361.1408.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ortho-Methoxyphenyl
4,6-O-4-methoxybenzylidene-2,3-dideoxy-α/β-D-erythro-hex-2-eno-C-pyranoside (3af)
Following the general procedure for the preparation of α-C-glycosides, the coupling between 1a
and 2f under the effect of CuBr•SMe2/ZnCl2 at 55 oC in a prolonged reaction time (10 h) provided
3af as a mixture α/β diastereomers with the α-isomer being the predominant product, which were
separated by silica gel column chromatography (petroleum ether/ethyl acetate = 20 : 1) for
23
detailed characterization. The pure β-3af was obtained as a colorless oil (10.6 mg, 15%): [α]D
=
+4.2 (c 2.13, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ 7.37 (d, J = 8.7 Hz, 2H), 7.33 – 7.27 (m,
2H), 7.03 (d, J = 8.1 Hz, 1H), 6.97 – 6.91 (m, 3H), 5.95 (d, J = 10.3 Hz, 1H), 5.79 (dt, J = 10.3,
2.1 Hz, 1H), 5.69 (s, 1H), 5.67 (t, J = 2.7 Hz, 1H), 4.37 – 4.35 (m, 1H), 4.21 (dd, J = 10.0, 4.6 Hz,
1H), 3.82 (t, J = 9.8Hz, 4H), 3.76 (s, 3H), 3.70 – 3.64 (m, 1H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 159.5, 156.0, 130.6, 130.1, 129.0, 127.8, 127.6, 127.2, 125.8, 120.4, 113.4, 111.0,
100.9, 74.2, 71.7, 71.2, 68.4, 55.5, 55.1; HRMS (ESI) m/z calcd for C21H23O5 [M + H]+: 355.1540;
found: 355.1537. Pure α-3af was obtained as a colorless oil (36.1 mg, 51%): [α]D23 = +12.9 (c
1.00, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ 7.37 – 7.34 (m, 3H), 7.33 – 7.30 (m, 1H), 7.05 (d,
J = 8.3 Hz, 1H), 6.98 (td, J = 7.4, 1.1 Hz, 1H), 6.92 – 6.90 (m, 2H), 6.12 (d, J = 9.5 Hz, 1H), 5.98
(dt, J = 10.4, 2.6 Hz, 1H), 5.65 (s, 1H), 5.60 (d, J = 2.6 Hz, 1H), 4.24 (d, J = 8.3 Hz, 1H), 4.10 (dd,
J = 10.2, 4.7 Hz, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.71 – 3.68 (m, 1H), 3.48 – 3.42 (m, 1H); 13C
ACS Paragon Plus Environment

Page 25 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
{1H}NMR (100 MHz, DMSO-d6) δ 159.5, 156.7, 130.1, 129.5, 129.2, 127.6 (2C), 127.4, 126.9,
120.0, 113.3, 111.4, 100.9, 74.4, 69.3, 68.5, 65.4, 55.5, 55.1; HRMS (ESI) m/z calcd for C21H23O5
[M + H]+: 355.1540; found: 355.1543.
9
meta-Methoxyphenyl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4,6-O-4-methoxybenzylidene-2,3-dideoxy-α/β-D-erythro-hex-2-eno-C-pyranoside (3ag)
Following the general procedure for the preparation of α-C-glycosides, the coupling between 1a
and 2g under the effect of CuBr•SMe2/ZnCl2 at 55 oC in a prolonged reaction time (10 h) provided
3ag (49.58 mg, 70%) as a colorless syrup in an inseparable mixture of α/β diastereomers with the
desired α-isomer being the predominant product (α/β = 4:1, determined by 1H NMR): [α]D
=
23
+3.4 (c 2.90, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ 7.40 – 7.28 (m, 3H), 6.98 (d, J = 7.8 Hz,
1H), 6.95 – 6.89 (m, 4H), 6.16 – 6.09 (m, 1.6H), 5.99 (d, J = 10.1 Hz, 0.2H), 5.84 – 5.81(m, 0.2H),
5.69 (s, 0.2H), 5.65 (s, 0.8H), 5.34 (d, J = 2.6 Hz, 1H), 4.38 (d, J = 8.4 Hz, 0.2H), 4.27 (d, J = 8.2
Hz, 0.8H), 4.21 (dd, J = 10.0, 4.5 Hz, 0.2H), 4.12 (dd, J = 10.2, 4.7 Hz, 0.8H), 3.84 – 3.74 (m, 7H),
3.42 – 3.36 (m, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 159.5, 159.4, 141.3, 131.2, 130.0,
129.6, 129.5, 127.6, 127.1, 125.9, 119.2, 113.4, 113.3, 113.1, 112.9, 100.9, 77.3, 74.2, 74.1, 73.9,
71.1, 68.4, 65.5, 55.1 (2C); HRMS (ESI) m/z calcd for C21H22O5Na [M + Na]+: 377.1359; found:
377.1357.
para-Methoxyphenyl
4,6-O-4-methoxybenzylidene-2,3-dideoxy-α/β-D-erythro-hex-2-eno-C-pyranoside (3ah)
Following the general procedure for the preparation of α-C-glycosides, the coupling between 1a
and 2h under the effect of CuBr•SMe2/ZnCl2 at 55 oC in a prolonged reaction time (10 h) provided
3ah (53.12 mg, 75%) as a colorless oil in an inseparable mixture of α/β diastereomers (α/β = 5.2 :
1, determined by 1H NMR): [α]D23 = +8.5 (c 2.13, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ 7.36
– 7.30 (m, 4H), 7.00 – 6.95 (m, 2H), 6.91 – 6.89 (m, 2H), 6.13 – 6.05 (m, 1.68H), 5.99 (d, J = 10.4
Hz, 0.16H), 5.81 – 5.75 (m, 0.16H), 5.68 (s, 0.16H), 5.64 (s, 0.84H), 5.31 (d, J = 2.4 Hz, 1H), 4.36
(d, J = 8.4 Hz, 0.16H), 4.26 (d, J = 8.4 Hz, 0.84H), 4.19 (dd, J = 10.2, 4.6 Hz, 0.16H), 4.03 (dd, J
= 10.2, 4.6 Hz, 0.84H), 3.76 (s, 3H), 3.74 (s, 3H), 3.72 (d, J = 10.4 Hz, 0.84H), 3.67 – 3.64 (m,
0.16H), 3.42 – 3.35 (m, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 159.5, 158.9, 131.6, 130.1,
129.6, 129.0, 128.6, 127.6, 127.1, 113.8, 113.3, 100.9, 74.4, 73.8, 68.5, 64.8, 55.1; HRMS (ESI)
m/z calcd for C21H22O5Na [M + Na]+: 377.1359; found: 377.1356.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 44
1
2
3
4
para-Fluorophenyl
5
6
7
8
4,6-O-4-methoxybenzylidene-2,3-dideoxy-α/β-D-erythro-hex-2-eno-C-pyranoside (3aj)
Following the general procedure for the preparation of α-C-glycosides, the coupling between 1a
and 2j under the effect of CuBr•SMe2/ZnCl2 provided 3aj as a mixture of α/β diastereomers (α/β =
3.5 : 1), which were separated by silica gel column chromatography (petroleum ether/ethyl acetate
= 15 : 1). The pure β-3aj was obtained as a white solid (14.4 mg, 21%): [α]D23 = +4.3 (c 1.93,
CHCl3); 1H NMR (400 MHz, DMSO-d6) δ 7.41 – 7.36 (m, 4H), 7.20 (t, J = 8.9 Hz, 2H), 6.94 –
6.84 (m, 2H), 6.01 (d, J = 10.3 Hz, 1H), 5.82 (dt, J = 10.4, 2.1 Hz, 1H), 5.68 (s, 1H), 5.39 (s, 1H),
4.38 (dd, J = 7.5, 3.4 Hz, 1H), 4.20 (dd, J = 10.0, 4.6 Hz, 1H), 3.80 (t, J = 10.3 Hz, 1H), 3.76 (s,
3H), 3.68 – 3.63 (m, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 161.7 (d, JC−F = 244.8 Hz),
159.5, 136.4 (d, JC−F = 3.0 Hz), 131.0, 130.1, 129.2 (d, JC−F = 8.4 Hz), 127.6, 126.1, 115.2 (d, JC−F
= 21.5 Hz), 113.4, 100.9, 76.7, 74.1, 71.2, 68.4, 55.1; HRMS (ESI) m/z calcd for C20H20FO4 [M +
H]+: 343.1340; found: 343.1343. The pure α-3aj was obtained as a white solid (49.3 mg, 72%):
[α]D23 = +10.3 (c 3.25, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ 7.47 – 7.44 (m, 2H), 7.33 (d, J
= 8.7 Hz, 2H), 7.23 (t, J = 8.9 Hz, 2H), 6.91 – 6.89 (m, 2H), 6.13 (t, J = 11.1 Hz, 2H), 5.65 (s, 1H),
5.38 (s, 1H), 4.29 – 4.26 (m, 1H), 4.09 (dd, J = 10.2, 4.6 Hz, 1H), 3.77 – 3.72 (m, 4H), 3.39 – 3.34
(m, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 161.7 (d, JC−F = 244.9 Hz), 159.5, 136.0 (d, JC−F
= 3.0 Hz), 130.0, 129.5 (d, JC−F = 8.3Hz), 129.4, 127.6, 127.4, 115.3 (d, JC−F = 21.3 Hz), 113.4,
101.0, 74.2, 73.4, 68.4, 65.1, 55.1; HRMS (ESI) m/z calcd for C20H20FO4 [M + H]+: 343.1340;
found: 343.1344.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 4,6-O-(di-tert-butyl)silylene-2,3-dideoxy-α/β-D-C-erythro-hex-2-enopyranoside (3ba)
Following the general procedure for the synthesis of α-C-glycosides, the coupling between 1b and
2a under the effect of CuBr•SMe2/ZnCl2 provided 3ba (49.96 mg, 88%) as a colorless oil in a
mixture of α/β isomers (α/β = 4.5:1). An aliquot of pure α-3ba was obtained for detailed
23
characterization: [α]D = +3.6 (c 0.25, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.83 (dt, J = 10.3,
1.8 Hz, 1H), 5.63 (dt, J = 10.5, 2.4 Hz, 1H), 4.40 – 4.32 (m, 2H), 4.13 (dd, J = 9.9, 5.0 Hz, 1H),
3.84 (t, J = 10.1 Hz, 1H), 3.55 – 3.49 (m, 1H), 1.28 (d, J = 6.8 Hz, 3H), 1.05 (s, 9H), 0.99 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3) δ 130.5, 129.6, 70.5, 70.2, 68.4, 67.7, 27.6, 27.2, 22.8, 20.2,
19.4; HRMS (ESI) m/z calcd for C15H29O3Si [M + H]+: 285.1881; found: 285.1883.
Phenyl 4,6-O-(di-tert-butyl)silylene-2,3-dideoxy-α/β-D-C-erythro-hex-2-enopyranoside (3bd)
ACS Paragon Plus Environment

Page 27 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Following the general procedure for the synthesis of α-C-glycosides, the coupling between 1b and
2d under the effect of CuBr•SMe2/ZnCl2 provided 3bd (51.2 mg, 74%) as a white solid in a
mixture of α/β isomers (α/β = 4.3:1). As the major product, an aliquot of pure α-3bd was obtained
for detailed characterization: [α]D23 = +4.1 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.39 –
7.33 (m, 5H), 6.11 (dt, J = 10.4, 1.9 Hz, 1H), 5.94 (dt, J = 10.4, 2.6 Hz, 1H), 5.24 (q, J = 2.6 Hz,
1H), 4.50 – 4.46 (m, 1H), 4.02 (dd, J = 9.9, 5.0 Hz, 1H), 3.85 (t, J = 10.2 Hz, 1H), 3.57 – 3.51 (m,
1H), 1.06 (s, 9H), 0.95 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 139.6, 131.5, 128.6, 128.2,
128.1, 127.2, 75.1, 70.6, 68.4, 67.5, 27.6, 27.2, 22.9, 20.2; HRMS (ESI) m/z calcd for C20H31O3Si
[M + H]+: 347.2037; found: 347.2039.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Methylphenyl 4,6-O-(di-tert-butyl)silylene-2,3-dideoxy-α/β-D-C-erythro-hex-2-enopyranoside
(3be)
Following the general procedure for the synthesis of α-C-glycosides, the coupling between 1b and
2e under the effect of CuBr•SMe2/ZnCl2 provided 3be (56.9 mg, 79%) as a white solid in a
mixture of α/β isomers (α/β = 5.2 : 1, determined by 1H NMR). The α/β isomers of 3be were
23
inseparable by silica gel column chromatography, thus were characterized as a mixture: [α]D
=
+22.5 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.26 (m, 2.5H), 7.25 – 7.18 (m,
1.5H), 6.18 (d, J = 10.4 Hz, 0.84H), 6.02 (d, J = 10.4 Hz, 0.16H), 5.93 – 5.89 (m, 0.84H), 5.79 –
5.75 (m, 0.16H), 5.48 (q, J = 3.0 Hz, 0.16H), 5.46 (q, J = 2.6 Hz, 0.84H), 4.63 – 4.60 (m, 0.16H),
4.52 – 4.48 (m, 0.84H), 4.24 (dd, J = 9.8, 5.0 Hz, 0.16H), 3.97 (t, J = 10.3 Hz, 0.16H), 3.95 – 3.92
(m, 0.84H), 3.84 (t, J = 10.1 Hz, 0.84H), 3.82 – 3.75 (m, 0.16H), 3.54 – 3.48 (m, 0.84H), 2.46 (s,
2.55H), 2.42 (s, 0.45H), 1.11 (s, 1.45H), 1.09 (s, 7.55H), 1.06 (s, 1.45H), 0.97 (s, 7.55H); 13C{1H}
NMR (100 MHz, CDCl3) δ 138.3, 138.0, 136.9, 136.2, 131.7, 131.0, 130.9, 130.1, 128.9, 128.5,
128.3, 127.6, 126.4, 125.4, 75.7, 75.6, 72.2, 70.9, 70.4, 68.1, 67.5, 67.4, 27.7, 27.6, 27.3, 27.2,
22.9 (2C), 20.3, 20.2, 19.2 (2C); HRMS (ESI) m/z calcd for C21H33O3Si [M + H]+: 361.2194;
found: 361.2199.
4-Methylphenyl 4,6-O-(di-tert-butyl)silylene-2,3-dideoxy-α/β-D-C-erythro-hex-2-enopyranoside
(3bi)
Following the general procedure for the synthesis of α-C-glycosides, the coupling between 1b and
2i under the effect of CuBr•SMe2/ZnCl2 at 55 oC in an extended reaction time (10 h) provided 3bi
as a mixture of α/β diastereomers, which was separated by silica gel column chromatography
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 44
1
2
3
4
5
6
7
8
9
(petroleum ether/ethyl acetate = 100 : 1). The pure β-3bi was obtained as a white solid for detailed
characterization (12.9 mg, 18%): [α]D23 = +40.0 (c 0.43, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.21 (d, J = 7.9 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 5.96 (dt, J = 10.3, 1.9 Hz, 1H), 5.72 (dt, J =
10.3, 1.9 Hz, 1H), 5.19 (d, J = 2.4 Hz, 1H), 4.58 – 4.54 (m, 1H), 4.21 (dd, J = 10.0, 5.0 Hz, 1H),
3.93 (t, J = 10.3 Hz, 1H), 3.74 – 3.68 (m, 1H), 2.33 (s, 3H), 1.07 (s, 9H), 1.02 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3) δ 138.2, 137.3, 129.9, 129.6, 129.4, 127.5, 78.1, 75.5, 70.4, 67.4, 27.7,
27.3, 22.9, 21.3, 20.2; HRMS (ESI) m/z calcd for C21H32O3SiNa [M + Na]+: 383.2013; found:
383.2015. The pure α-3bi was also obtained (51.9 mg, 72%) as a white solid for full
characterization: [α]D23 = -6.0 (c 0.85, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 7.8 Hz,
2H), 7.17 (d, J = 7.9 Hz, 2H), 6.07 (dt, J = 10.4, 1.8 Hz, 1H), 5.89 (dt, J = 10.5, 2.5 Hz, 1H), 5.18
(d, J = 2.6 Hz, 1H), 4.46 – 4.43 (m, 1H), 3.98 (dd, J = 9.9, 5.0 Hz, 1H), 3.81 (t, J = 10.1 Hz, 1H),
3.55 – 3.49 (m, 1H), 2.35 (s, 3H), 1.04 (s, 9H), 0.93 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ
138.1, 136.5, 131.3, 129.3, 128.2, 127.4, 75.0, 70.6, 68.2, 67.5, 27.6, 27.2, 22.9, 21.3, 20.2;
HRMS (ESI) m/z calcd for C21H32O3SiNa [M + Na]+: 383.2013; found: 383.2014.
4-Fluorophenyl 4,6-O-(di-tert-butyl)silylene-2,3-dideoxy-α/β-D-C-erythro-hex-2-enopyranoside
(3bj)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Following the general procedure for the synthesis of α-C-glycosides, the coupling between 1b and
2j under the effect of CuBr•SMe2/ZnCl2 provided 3bj (60.5 mg, 83%) as a white solid in a
mixture of α/β isomers (α/β = 5.6 : 1, determined by 1H NMR). The α/β isomers of 3bj were
23
inseparable by the silica gel column chromatography, thus were characterized as a mixture: [α]D
= +7.2 (c 1.93, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.28 (m, 2H), 7.09 – 7.00 (m, 2H),
6.12 (d, J = 10.4 Hz, 0.85H), 5.98 (d, J = 10.2 Hz, 0.15H), 5.91 (dt, J = 10.4, 2.5 Hz, 0.85H), 5.70
(dt, J = 10.3, 2.0 Hz, 0.15H), 5.21 (s, 1H), 4.56 (d, J = 8.7 Hz, 0.15H), 4.47 (d, J = 8.6 Hz, 0.85H),
4.22 (dd, J = 10.0, 5.1 Hz, 0.15H), 3.99 (dd, J = 9.9, 5.1 Hz, 0.85H), 3.93 (t, J = 10.3 Hz, 0.15H),
3.83 (t, J = 10.2 Hz, 0.85H), 3.75 – 3.69 (m, 0.15H), 3.50 – 3.44 (m, 0.85H), 1.08 (s, 1.35H), 1.06
(s, 7.65H), 1.02 (s, 1.35H), 0.95 (s, 7.65H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.7 (d, JC−F
247.8 Hz), 135.4 (d, JC−F = 3.2 Hz), 131.8, 130.3, 130.0 (d, JC−F = 8.2 Hz), 129.3, 129.2, 127.0,
=
115.5 (d, JC−F = 21.5 Hz), 74.4, 70.5, 70.3, 68.2, 67.4, 27.6 (2C), 27.2 (2C), 22.9, 22.8, 20.2 (2C);
HRMS (ESI) m/z calcd for C20H33FNO3Si [M + NH4]+: 382.2208; found: 382.2207.
Methyl 4,6-di-O-benzyl-2,3-dideoxy-α/β-D-C-erythro-hex-2-enopyranoside (3ca)
ACS Paragon Plus Environment

Page 29 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Following the general procedure for the synthesis of α-C-glycosides, the coupling between 1c and
2a under the effect of CuBr•SMe2/ZnCl2 provided 3ca (44.1 mg, 68%) as a colorless oil in a
mixture of α/β diastereomers (α/β = 1 : 1). An aliquot of pure α-3ca was obtained for detailed
characterization: [α]D23 = +19.5 (c 0.65, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.22 (m,
10H), 5.84 (dt, J = 10.4, 2.0 Hz, 1H), 5.76 (dt, J = 10.4, 2.0 Hz, 1H), 4.57 (dd, J = 11.9, 5.2 Hz,
2H), 4.50 (d, J = 12.3 Hz, 1H), 4.45 (d, J = 11.6 Hz, 1H), 4.38 – 4.33 (m, 1H), 3.94 (dd, J = 7.0,
2.2 Hz, 1H), 3.79 (dt, J = 7.4, 4.0 Hz, 1H), 3.67 – 3.60 (m, 2H), 1.26 (d, J = 6.8 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 138.4 (2C), 133.2, 128.5 (2C), 128.1, 128.0, 127.8, 127.7, 124.9, 73.5,
71.1, 71.0, 70.1, 69.4, 68.7, 19.2; HRMS (ESI) m/z calcd for C21H25O3 [M + H]+: 325.1798; found:
325.1800.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl 4,6-di-O-benzyl-2,3-dideoxy-α/β-D-C-erythro-hex-2-enopyranoside (3cb)
Following the general procedure for the synthesis of α-C-glycosides, the coupling between 1c and
2b under the effect of CuBr•SMe2/ZnCl2 provided 3cb (47.3 mg, 70%) as a colorless syrup in a
mixture of α/β diastereomers (α/β = 1.2 : 1). An aliquot of pure α-3cb was obtained for detailed
characterization: [α]D23 = +18.0 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.23 (m,
10H), 5.88 (dt, J = 10.4, 2.0 Hz, 1H), 5.82 (dt, J = 10.4, 1.9 Hz, 1H), 4.62 – 4.44 (m, 4H), 4.09 –
4.04 (m, 1H), 3.99 – 3.96 (m, 1H), 3.77 (dt, J = 7.3, 4.0 Hz, 1H), 3.69 – 3.62 (m, 2H), 1.72 – 1.65
(m, 1H), 1.54 – 1.48 (m, 1H), 0.98 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.4
(2C), 132.0, 128.5 (2C), 128.1, 128.0, 127.8, 127.7, 125.2, 74.0, 73.5, 71.2, 71.1, 70.3, 69.5, 26.5,
10.7; HRMS (ESI) m/z calcd for C22H27O3 [M + H]+: 339.1955; found: 339.1958.
Phenyl 4,6-di-O-benzyl-2,3-dideoxy-α/β-D-C-erythro-hex-2-enopyranoside (3cd)
Following the general procedure for the preparation of α-C-glycosides, the coupling between 1c
and 2d under the effect of CuBr•SMe2/ZnCl2 provided 3cd (58.0 mg, 75%) as a colorless oil in a
mixture of α/β isomers with the α-3cd as the predominant product (α/β = 4.8:1). An aliquot of
pure α-3cd was obtained for detailed characterization: [α]D23 = +25.0 (c 0.75, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.41 – 7.39 (m, 2H), 7.32 – 7.28 (m, 5H), 7.26 – 7.20 (m, 8H), 6.12 – 6.04
(m, 2H), 5.27 (t, J = 2.3 Hz, 1H), 4.56 (dd, J = 14.2, 11.8 Hz, 2H), 4.43 (dd, J = 14.6, 11.8 Hz,
2H), 4.15 (dq, J = 7.7, 1.8 Hz, 1H), 3.68 – 3.63 (m, 2H), 3.60 – 3.55 (m, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 139.7, 138.4, 138.3, 129.7, 128.5 (2C), 128.4, 128.2, 128.1, 128.0, 127.9, 127.7,
127.3, 74.3, 73.4, 71.3, 70.8, 70.3, 69.3; HRMS (ESI) m/z calcd for C26H27O3 [M + H]+: 387.1955;
ACS Paragon Plus Environment