Highly regioselective and stereoselective synthesis of C-Aryl glycosidesvianickel-catalyzedortho-C-H glycosylation of 8-aminoquinoline benzamides

Article abstract of DOI:10.1039/d1cc03589d

C-Aryl glycosides are of high value as drug candidates. Here a novel and cost-effective nickel catalyzedortho-C_Ar-H glycosylation reaction with high regioselectivity and excellent α-selectivity is described. This method shows great functional group compatibility with various glycosides, showing its synthetic potential. Mechanistic studies indicate that C-H activation could be the rate-determining step.

Full text of DOI:10.1039/d1cc03589d

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Highly regioselective and stereoselective synthesis
of C-Aryl glycosides via nickel-catalyzed ortho-C–
H glycosylation of 8-aminoquinoline benzamides†
Cite this: DOI: 10.1039/d1cc03589d
Received 5th July 2021,
Accepted 9th August 2021
Wei-Yu Shi, Ya-Nan Ding, Nian Zheng, Xue-Ya Gou, Zhe Zhang, Xi Chen,
Yu-Yong Luan, Zhi-Jie Niu and Yong-Min Liang
*
DOI: 10.1039/d1cc03589d
rsc.li/chemcomm
C-Aryl glycosides are of high value as drug candidates. Here a novel glycosyl precursors and metallated arenes.7 However, these meth-
and cost-effective nickel catalyzed ortho-CAr–H glycosylation ods show poor functional group tolerance and low stereo-
reaction with high regioselectivity and excellent a-selectivity is selectivity. In addition to traditional organic synthetic methods,
described. This method shows great functional group compatibility transition metal-catalyzed cross-coupling reactions, such as Stille,8
with various glycosides, showing its synthetic potential. Mecha- Negishi,9 Suzuki–Miyaura10 and other cross-coupling reactions
nistic studies indicate that C–H activation could be the rate- have been well developed for synthesizing C-Aryl glycosides over
determining step.
the past few decades.11 These approaches always require high
active pre-functioned coupling partners. In recent years, C–H
Glycosides are crucial structural motifs that broadly exist in activation has been widely used in synthetic chemistry as an
biological and pharmaceutical chemistry.1 Compared with O- or effective strategy to construct C–C bonds.12 Several groups have
N-glycosides, C-glycosides, in which the C–O/C–N is replaced by a reported some efficient methods to synthesize C-glycosides via a
C–C bond, exhibit enhanced stability in vivo and in vitro. C-Aryl transition-metal-catalyzed C–H activation strategy.13 Ye and co-
glycosides, as a privileged class of C-glycosides, are widely found in workers established a Pd-catalyzed, N-quinolyl-group-directed,
various bioactive natural products and drug candidates.1,2 As an ortho-C–H functionalization of benzoic acid derivatives and 1-
example, a-C-Mannosyltryptophan3 (C-Man-Trp) was the first case iodoglycals in 2016.14 Then, in 2019, Chen’s work disclosed a
of a C-glycosyl amino acid found in proteins from human urine. stereoselective synthesis of C-aryl glycosides via palladium-
Vitexin2 and isovitexin are C-glycosyl flavonoids existing in the catalyzed ortho-directed C(sp2)–H functionalization by using arenes
plant kingdom. Another isoflavone C-glycoside, puerarin,4 which is or heteroarenes with glycosyl chlorides.15 Although these synthetic
isolated from Chinese herbal medicine Pueraria lobota, has been routes have been widely explored to construct C-Aryl glycosides
used to reduce febrile symptoms and against inebriation. Further- with great stereoselectivity, the regioselectivity of the products has
more, antitumor angucycline antibiotic Derhodinosylurdamycin not been well controlled. Both mono- and di-mannosylated pro-
A,2,5 antidiabetic agent Dapagliflozin2 and an IMP (inosine 50- ducts were observed in the reaction. Therefore, to solve this
monophosphate dehydrogenase) dehydrogenase inhibitor Benza- problem, developing
a novel and cost-effective transition-
mide Riboside6 also contain aryl aglycone skeletons. Therefore, metal-catalyzed ortho-CAr–H glycosylation method with highly
methods towards a highly regioselective and stereoselective synth- regioselectivity and stereoselectivity is extremely challenging
esis of C-Aryl glycosides have attracted great attention from (Fig. 1 and 2).
chemists, which could provide an effective strategy for drug design
in modern chemistry.
Herein, we have reported a highly regioselective and stereo-
selective ortho-C–H glycosylation of 8-aminoquinoline amides
General methods for the CAr–H glycosylation reaction include by using a cost-effective nickel catalyst. In this reaction, glycosyl
the classical Friedel–Crafts-type arylation of glycosides with chloride, as the coupling partner, exhibited great reaction
electron-rich arenes and nucleophilic substitution between activity. Only mono-substituted rather than di-substituted pro-
ducts were observed when both of the ortho-positions on the
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou
phenyl were exposed. Meanwhile, most products showed exclu-
sive a-selectivity and good yields.
730000, P. R. China. E-mail: liangym@lzu.edu.cn
† Electronic supplementary information (ESI) available: Details on the experi-
To initiate this study, we have chosen benzamide 1a, con-
mental procedure, and characterization data of all compounds. CCDC 2086454
taining directing group 8-aminequinoline, and mannofurano-
(3q). CCDC of single crystal X-ray data of compound. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/d1cc03589d
syl chloride donor 2a as the standard substrates for the
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in dioxane at 140 1C under Ar atmosphere, and the expected
product 3a afforded exclusive a-selectivity which was isolated in
61% yield.
With the optimized reaction conditions in hand, we next
investigated the scope and limitations of this Ni-catalyzed
C–H glycosylation reaction by systematically varying the
nature of the benzamides and the sugars. We first explored
the substrate scope of benzamides as shown in Scheme 1. To
our delight, aromatic amides with ortho-(3b and 3c), meta-
(3d–3i), para-(3j–3s) or di-substituted (3x) groups all gave
corresponding products with regioselectivity and a-
stereoselectivity in moderate to good yields besides product
3f, which produced two isomers with an a/b ratio of 5 : 1, and
the different substituent groups including electron-donating
as well as electron-withdrawing were well tolerated. The
structure of 3q was confirmed by single crystal X-ray diffrac-
tion analysis and the a-anomeric configuration of other
products was also determined using 1D- and 2D-NMR. Sev-
eral hindered benzo-heterocycles and heterocyclic amides
were compatible with the reaction conditions, providing C-
aryl glycosides 3t–3u with perfect control of the a-selectivity
in 65% and 26% yields, respectively. It worked smoothly
when we used benzamides substituted on the quinoline ring
and the desired products (3v and 3w) were obtained in
moderate to good yields.
Fig. 1 Examples of natural and bioactive C-glycosides.
To further investigate the substrate scope, several glycosyl
chlorides were explored in the reaction. As depicted in
Scheme 1, more than three types of sugars could successfully
provide corresponding C-Aryl glycosides with regioselectivity.
Fig. 2 Previous works and our strategy for synthesizing C-Aryl glycosides. The pyranosides derived from L-rhamnose and D-mannose
showed poor reactivity under standard reaction conditions,
giving the desired C-Aryl glycosides with exclusive a-selectivity
optimization of the reaction conditions (see Table S1 in ESI†).
Preliminary experimental results showed that when benzamide
1a (0.1 mmol) was reacted with mannofuranosyl chloride 2a
(0.2 mmol) in the presence of Ni2CO3 (0.005 mmol) as a catalyst
and KHCO3 (0.2 mmol) as a base in dioxane at 140 1C under an
Ar atmosphere for 16 h, the desired product 3a was not
observed (see entry 1 in Table S1, ESI†). Other commercial
nickel catalysts were screened, and Ni(dppf)Cl2 was found to be
the most suitable for this reaction, which delivered the product
3a in 38% yield (see entries 2–5 in Table S1, ESI†). Thereafter,
various solvents were also tested, and dioxane showed the best
performance (see entries 6–10 in Table S1, ESI†). It was worth
noting that a significant increase in the yield of 3a was observed
when we adjusted the amount of benzamide 1a and mannofur-
anosyl chloride 2a to 2 : 1 (see entry 11 in Table S1, ESI†).
Among the bases examined, it turned out that the base effect
was also critical and KHCO3 was superior to other bases
(see entries 12–17 in Table S1, ESI†). In addition, the control
experiments showed that no reaction took place in the
absence of a Ni catalyst and base, indicating that catalyst and
base were necessary for the reaction (see entries 6 and 18 in
Table S1, ESI†).
(4d and 4e) only in 21% and 19% yields. In addition,
D-mannosyl chloride (4f) protected by the methoxy group
(OMe), D-galactosyl chloride (4g) and D-glucosyl chloride (4h)
protected by the benzyl group (OBn) did not work well in this
reaction. Compared to D-mannosyl chloride and L-rhamnosyl
chloride, D-ribofuranosyl chloride, protected by different sub-
stituent groups on the C-5 position, afforded excellent
b-selective products (4a–4c) in moderate yields. Notably, When
the C-5 position of D-ribofuranosyl chloride was protected by
the allyl group, the corresponding product was not afforded.
And a product of 1,2 alkenyl shift was obtained in 27% yield
and showed a 5 : 1 b/a stereochemistry. Previous reports indi-
cated that trans-olefins usually were observed rather than the
cis-product as we got.16
A series of experiments were conducted to shed more light
on the nickel catalyzed ortho-CAr–H glycosylation reaction.
When 2.0 equiv. radical scavengers were added to the reaction
under standard conditions, it was observed that neither 2,2,6,
6-tetramethyl-1-piperidinyloxy (TEMPO), butylated hydroxylto-
luene (BHT) nor 1,1-diphenylene (DPE) had a significant inhi-
bitory effect on the reaction. These results indicated that a free
radical process did not appear to be involved in the reaction.
Subsequently, isotopically labeled compound D5-1a was reacted
without sugar for 4 hours under otherwise standard conditions,
Finally, the optimized conditions were determined to be
reacting 1a (0.2 mmol) with 2a (0.1 mmol), KHCO3 (0.2 mmol)
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Scheme 1 Substrates scope of the C-Aryl glycosylation reactiona. Reaction conditions: 1a (0.2 mmol, 2.0 equiv.), 2a (0.1 mmol), Ni(dppf)Cl2 (5 mol%),
KHCO3 (0.2 mmol, 2.0 equiv.), 1,4-dioxane (0.5 mL), 140 1C, 16 h and Ar. Isolated yields are given. The ratio of a and b anomers was determined using
crude 1H NMR.
and
a little amount of H/D exchange occurred at the
ortho-position which suggested that the C–H activation was
reversible. The kinetic isotope effect (KIE) was obtained from
an intermolecular competition experiment by using a mixture
of 1a and D5-1a17 with a ratio of 1 : 1 under standard conditions.
The KIE value of 3.7 demonstrated that the ortho-C–H activa-
tion would be the rate-determining step. Finally, it was worth
mentioning that 3a reacted with NaOH in EtOH at 130 1C for
20 h to give derivative 5a containing a carboxyl group in 71%
yield (Scheme 2).
On the basis of the above experimental result and relevant
literature,18
a proposed catalytic cycle is illustrated in
Scheme 3. Initially, the reaction begins with the coordination
of amide A and Ni(II) catalyst. Subsequently, ligand exchange
and reversible cleavage of the ortho C–H bond with the help of a
base are undergone to give Ni(II) species B. After the oxidative
addition of the C–Cl bond in a-glycosyl chloride C to the nickel
center, the intermediate D is given. Another possible pathway19
involves the oxocarbenium ion generated from a-glycosyl chlor-
ide C with the activation of Ni as a Lewis acid being attacked by
Ni complex B from the a-face to give intermediate D. Reductive
elimination from complex D followed by protonation gives
complex E. Finally, complex E undergoes demetallization to
form product F with the regeneration of Ni(II) for the next cycle.
In summary, we have reported the successful development
of a highly regioselective and stereoselective process for the
glycosylation of C–H bonds. The method for synthesizing C-Aryl
glycosides may have potential application value in drug
Scheme 2 Mechanism research and Hydrolysis experiment.
molecular design. The reaction has good functional group
tolerance and exhibits excellent a-selectivity and regioselectiv-
ity. The hydrogen-deuterium exchange experiment shows that
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Conflicts of interest
There are no conflicts to declare.
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