Stereocontrolled Synthesis of 2-Deoxy- C-glycopyranosyl Arenes Using Glycals and Aromatic Amines

Article abstract of DOI:10.1021/acs.orglett.8b01117

An efficient and stereoselective one-pot, two-step tandem α-arylation of glycals from readily available aryl amines via stable diazonium salts has been developed. Moreover, the stereoselective preparation of the challenging β-C-glycosyl arenes by the anomerization of α-C-glycosides using HBF₄ is also described. This protocol has a broad substrate scope and a wide functional-group tolerance. It can be used for the gram-scale preparation of 3-oxo-C-glycosides, which are versatile substrates for the preparation of many biologically important C-glycosides.

Full text of DOI:10.1021/acs.orglett.8b01117

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereocontrolled Synthesis of 2‑Deoxy‑C‑glycopyranosyl Arenes
Using Glycals and Aromatic Amines
Shengbiao Tang,†,‡ Qiannan Zheng,† De-Cai Xiong,*,†,§ Shende Jiang,‡ Qin Li,† and Xin-Shan Ye*,†
†State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No.
38, Beijing 100191, China
‡School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
§State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031,
China
S
* Supporting Information
ABSTRACT: An efficient and stereoselective one-pot, two-step tandem α-arylation of glycals from readily available aryl amines
via stable diazonium salts has been developed. Moreover, the stereoselective preparation of the challenging β-C-glycosyl arenes
by the anomerization of α-C-glycosides using HBF4 is also described. This protocol has a broad substrate scope and a wide
functional-group tolerance. It can be used for the gram-scale preparation of 3-oxo-C-glycosides, which are versatile substrates for
the preparation of many biologically important C-glycosides.
Scheme 1. Some Bioactive 2-Deoxy-C-glycosyl Compounds
and Their Transition-Metal-Catalyzed Synthetic Methods
he C-glycopyranosyl motif is present in numerous
Tbiologically active compounds and drugs such as
angucyclines, marmycin A−B, urdamycinones A−D, kidamycin,
pluramycin A, canagliflozin, dapagliflozin, and ipragliflozin
(Scheme 1a).1 A key carbon−carbon glycosidic bond between
the aglycon carbon and the anomeric carbon of the attached
carbohydrate confers remarkable stability against both enzymatic
and/or chemical hydrolysis, thus improving the physiological
efficacy of a bioactive compound. Therefore, carbon−carbon
glycosidic bond construction is one of the enduring and crucial
goals of organic synthesis.2 Transition-metal-catalyzed coupling
reactions are powerful tools for the construction of unique C-
glycosyl linkages.3 Especially, Heck-type arylations of glycals4
with arylboronic acids,5 triarylindium reagents,6 arylzinc
reagents,7 arylhydrazines,8 sodium arylsulphinates,9 aryl bro-
mides/iodides,10 aromatic acids,11 and others have been
developed.12 Indeed, all have now been extensively employed
as useful approaches for the synthesis of 2-deoxy-α-C-D-glycosyl
arenes (Scheme 1b). Nevertheless, these reactions suffer from
some limitations such as limited substrate scope, low yield, long
reaction time, or byproducts. Moreover, these transformations
are unable to generate 2-deoxy-β-D-glycosyl arenes, which are
naturally occurring C-glycosides. Therefore, the development of
more practical and stereoselective protocols for the synthesis of
2-deoxy-C-glycosyl arenes from readily accessible starting
materials still remains a challenge.
Aryl diazonium salts are ideal electrophilic partners for
palladium-catalyzed coupling reactions at room temperature
under mild conditions, especially for a Heck reaction of allylic
alcohols/esters.13 Glycals are somewhat similar to allylic
Received: April 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01117
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
alcohols/esters. However, diazonium salts are absent from C-
glycoside synthesis. The instability and explosive nature of the
salts might be the main restriction on their widespread
application. Nevertheless, the in situ diazotization of readily
available anilines is an alternative safe way to diazonium salts.14
So, we herein report a stereocontrolled protocol for the synthesis
of 2-deoxy-C-glycopyranosyl arenes from glycals and aromatic
amines (Scheme 1c).
Et2O complex (Table 1, entry 14, for more details on condition
screening, see Table S2 in the Supporting Information (SI)).
With the optimized reaction conditions in hand, a variety of
glycals were subjected to these arylation/anomerization
reactions (Scheme 2). The reactions of methylated glucal or
Scheme 2. C-Glycosylation of p-Anisidine (3) with Glycals
a
and Anomerization
We embarked on our investigation by studying the arylation of
glucal 1a with 4-methoxybenzenediazonium tetrafluoroborate
(2) in the presence of various Pd catalysts and additives at room
temperature for 1 h (Table 1). No arylation occurred utilizing
a,b
Table 1. Screening of the Reaction Conditions
entry
conditions
2, Pd(OAc)2
yield (%) of 4a yield (%) of 5a
1
2
3
4
5
6
7
8
9
α (0)
0
2, Pd(OAc)2, PPh3 (20%)
2, Pd(PPh3)4
α (34)
α (36)
α (33)
α (81)
α (74)
α (53)
α (56)
α (76)
α (0)
25
31
30
0
2, Pd(PPh3)4, Xanphose (20%)
2, Pd(dba)2
2, Pd(dba)2, PPh3 (20%)
2, Pd(dba)2, NaHCO3 (10 equiv)
2, Pd(dba)2, K2CO3 (10 equiv)
2, Pd(dba)2, HOAc (10 equiv)
3, Pd(dba)2, NaNO2, HBF4
3, Pd(dba)2, NaNO2, HBF4
3, Pd(dba)2, tBuONO, HBF4
3, Pd(dba)2, NOBF4
0
26
17
0
a
The C-glycosylation conditions (see Table 1, entry 13); the
c
anomerization conditions (see Table 1, entry 14); isolated yield.
10
0
c
c
c
,d
11
12
13
14
α (0)
0
α (0)
0
benzylated galactal/6-deoxy-glucal/rhamnal afforded the corre-
sponding α- or β-linked product in 57−92% yields. The tert-
butyldimethylsilyl protective group was well tolerated under the
arylation conditions (product 4cα), whereas the anomerization
product 4cβ was partially desilylated. It is noteworthy that the
reaction of benzylated L-arabinal with amine 3 could only
generate 4gβ, which is a thermodynamically stable arylation
product whose anomerization is forbidden.
Subsequently, we explored the scope of the aryl amines; the
results are summarized in Table 2. Aryl amines bearing both
electron-withdrawing and electron-donating substituents under-
went the reactions smoothly, affording the corresponding α-
products in moderate to good yields. The anomerization of 2-
deoxy-α-C-D-glycosyl arenes with electron-donating substituents
could provide the β-products in excellent yields (entries 4, 15).
To our delight, β-C-glycosides were accessed in moderate yields
from the arenes with electron-withdrawing substituents. The
ring-opened compound 6 was detected in 25% yield when α-C-D-
glycosyl para-bromobenzene (4iα) was converted to its β-
counterpart (4iβ). Interestingly, compound 6 was inert to the
anomerization conditions (Scheme 3A). This is quite a common
occurrence as the aryl moiety contains electron-withdrawing
substituents. To further demonstrate the practicality of this
newly developed method, the reaction of 3 and 1f was carried out
on 6.44 mmol scale (entry 15). Product 4fα was obtained in 58%
isolated yield (1.20 g). Anomerization of 4fα was performed on
3.68 mmol scale, and 4fβ was afforded in 98% isolated yield (1.18
g).
α (73)
β (92)
0
e
4aα, HBF4
0
a
Reaction conditions: 1a (21.0 mg, 0.05 mmol), Pd catalyst (0.0075
mmol), and 2 (22.0 mg, 0.1 mmol) in THF (4 mL) at room
b
c
temperature for 1 h. Isolated yield. 3 (31.0 mg, 0.25 mmol) and
NaNO2/Me3CNO2/NOBF4 (0.25 mmol) in THF (4 mL) at −40 °C
to room temperature for 30 min; then 1a (42.0 mg, 0.1 mmol) and
Pa(dba)2 (0.015 mmol) at room temperature for 1 h. MeOH as the
solvent. 4aα (10.0 mg) and HBF4-Et2O complex (50−75 μL) in Et2O
(1 mL) at room temperature for 1 h. PMP = p-methoxyphenyl.
d
e
Pd(OAc)2 as the catalyst (entry 1). The desired α-arylation
products 4aα (34% yield) and 5a (25% yield) were, however,
obtained in the presence of PPh3 (entry 2). The use of Pd(PPh3)4
as the catalyst, with or without Xanphose as the ligand, led to
similar results (entries 3−4). To our delight, only 4aα (81%
yield) was obtained when the reaction was catalyzed by Pd(dba)2
instead of Pd(PPh3)4 (entry 5). Further optimization studies of
other additives did not increase the yield of 4aα (Table 1, entries
6−9; Table S1, entries 1−19). Next, compound 2, generated in
situ by different methods from amine 3, was applied to the above
optimal conditions. After screening different diazotizing reagents
(entries 10−13), NOBF4 proved the best. Diazotization of amine
3 with NOBF4 in THF at 0 °C for 30 min, followed by the
treatment of glycal 1a and Pd(dba)2 at room temperature for 1 h,
gave 2-deoxy-α-D-glycosyl arene 4aα in 73% isolated yield (entry
13). By this point, we had established an efficient method to
produce α-C-glycosides via the arylation of glycals from aryl
amines. In addition, the α-C-glycosides could be further
transformed into β-C-glycosides through the action of HBF4-
The anomeric configurations were mainly confirmed by the
values of the J1,2 coupling constant. That is, a large J1,2 constant
was assigned for a 4C1 (D, β, >10 Hz), 1C4 (L, β, >10 Hz), or 1C4
(D, α, ∼9.5 Hz) conformer, and a small J1,2 constant (<7.0 Hz)
B
DOI: 10.1021/acs.orglett.8b01117
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Organic Letters
Letter
Table 2. C-Glycosylation of Glycals with Various Amines and
Anomerization
Scheme 3. Transformation of 4iα and 4fβ
a,b
4
1
was assigned for a C1 (D, α, <7.0 Hz) or C4 (L, α, <7.0 Hz)
conformer. Others were assigned on the basis of the NMR
spectra of known compounds or the 2D NMR spectra.
Next, the generated 2-deoxy-3-oxo-C-glycosides were trans-
formed into 3-hydroxy or 3-dimethylamino 2-deoxy-C-glyco-
sides (Scheme 3B), which are valuable C-glycosyl motifs in
bioactive natural products. Reduction of compound 4fβ using
NaBH4 afforded 42% yield of the alcohol 7 and 40% yield of the
alcohol 8 with no stereoselectivity. When LiBHEt3 was
employed, the alcohol 8 was obtained in 78% yield as a single
isomer. Treatment of 4fβ with NH4OAc and NaBH3CN formed
3-amino-C-glycoside, which was subsequently converted into the
expected 3-dimethylamino-C-glycoside 9 (50% yield) in the
presence of HCHO and NaBH3CN. The structures of
compounds 7, 8, and 9 were unambiguously identified by their
NMR analyses (Scheme S2 in the SI).
Although the formation mechanism of α-C-glycosides from
glycals and aryl diazonium salts via a Heck-type reaction is
clear,5,15 the details of this anomerization reaction are not yet
known. Thus, a plausible mechanism, based on the combination
of the previous work of Suzuki, Zou, and our group, through our
observations, is proposed (Scheme 4). We propose that HBF4
Scheme 4. Plausible Mechanism
activates the O5 oxygen, resulting in an endocyclic C1−O5 bond
cleavage to generate the acyclic oxocarbenium C (pathway A in
Scheme 4),2,16 which would prefer to produce the β-product via a
kinetic cyclization. If an electron-deficient aryl group is present,
HBF4 promotes activation of the O3 oxygen to produce the
stable byproduct D (pathway B in Schemes 4 and 3A).
In conclusion, for the first time, we have disclosed the one-pot,
two-step tandem α-arylation of glycals from readily available aryl
amines via a stable diazonium salt offering exclusive 3-oxo-α-C-
glycosides. Furthermore, the challenging β-C-glycosyl arenes can
be obtained from anomerization of α-C-glycosides in the
presence of HBF4. The protocols can be used for the gram-
scale preparation of the products and show a broad substrate
a
For the C-glycosylation conditions, see Table 1, entry 13; for the
b
anomerization conditions, see Table 1, entry 14. Isolated yield.
c
d
Gram-scale reaction. Amine 3 (2.0 g, 16.2 mmol, 2.5 equiv), 1f (2.0
g, 6.44 mmol), and Pa(dba)2 (0.97 mmol) were used at room
temperature for 3 h. Substrate 4fα (1.2 g, 3.68 mmol), HBF4 (2.5
mL), and Et2O (100 mL) were used at room temperature for 1.5 h.
e
C
DOI: 10.1021/acs.orglett.8b01117
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xinshan@bjmu.edu.cn.
*E-mail: decai@bjmu.edu.cn.
ORCID
Xin-Shan Ye: 0000-0003-4113-506X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by grants from the National
Natural Science Foundation of China (Grant No. 21572012,
21772006) and the State Key Laboratory of Drug Research
(SIMM1803KF-02).
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DOI: 10.1021/acs.orglett.8b01117
Org. Lett. XXXX, XXX, XXX−XXX