Palladium-Catalyzed Regioselective and Diastereoselective C-Glycosylation by Allyl-Allyl Coupling

Article abstract of DOI:10.1002/adsc.202001136

A Pd-catalyzed C-glycosylation reaction was developed by allyl-allyl coupling process using Achmatowicz rearrangement products as donors and methylcoumarins as acceptors under mild conditions. This method featured regio- and diastereoselectivities, stereo

Full text of DOI:10.1002/adsc.202001136

Title: Palladium-Catalyzed Regio- and Diastereoselective C-
Glycosylation by Allyl-Allyl Coupling
Authors: Junhao Li, Nan Zheng, Xuelun Duan, Rui Li, and Wangze
Song
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001136
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10.1002/adsc.202001136
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Palladium-Catalyzed Regio- and Diastereoselective C-
Glycosylation by Allyl-Allyl Coupling
Junhao Li,a Nan Zheng,a* Xuelun Duan,a Rui Li,a and Wangze Songa*
a
State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian,
116024, P. R. China
E-mail: nzheng@dlut.edu.cn, wzsong@dlut.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
through Achmatowicz rearrangement products (with
developed by allyl-allyl coupling process using acetate as the leaving group) and arylboronic acids by
Abstract. A Pd-catalyzed C-glycosylation reaction was
Achmatowicz rearrangement products as donors and
methylcoumarins as acceptors under mild conditions. This
method featured regio- and diastereoselectivities,
stereodivergent synthesis of C-glycosides. The glycosyl
donors with controlled stereodiversity and glycosyl
acceptors with fluorescent performace further highlighted
this methodology.
aryl-allyl coupling reaction albeit the ambiguous
mechanism and uncontrolled diastereoselectivities[6]
(Scheme 1b). Inspired by O’Doherty and Tong’s
work, we rationalized that using more bulky and
easily leaving tert-butylcarbonate group instead of
acetate group in Achmatowicz rearrangement
products could well control the diastereoselectivities
of C-alkyl glycosylation reaction.[4,5] However, it is
more difficult to realize C-alkyl than C-aryl
glycosylation due to the limited alkyl nucleophiles as
glycosyl acceptors exhibiting low reactivity and
Keywords: C-glycosylation; Allyl-allyl coupling; Pd-π-
allyl intermediate; Achmatowicz rearrangement products;
Methylcoumarins
uncontrolled
regio-
/diastereoselectivities.
Encouraged by the advancement of C-glycosylation
via Pd-π-allyl intermediate,[6,7] we envisioned that
methylcoumarins may be the ideal glycosyl acceptors
C-glycopyranosides are very attractive scaffolds
and widely exist in various natural products,
pharmaceutical molecules and fine chemicals because
of their unique stability under enzymatic or acidic
environments.[1] For example, aquayamycin and
medermycin containing C-glycopyranosides isolated
from organisms exhibit significant bioactivities.[2a]
Dapagliflozin, canagliflozin, and empagliflozin are
used as sodium/glucose contransporter-2 (SGLT 2)
inhibitors against type-II diabetes.[2b] Pro-Xylane is a
popular antiaging cosmetic agent.[2c] However,
compared to O- and N-glycosylation, it remains
challenging for regio- and diastereoselective
synthesis of C-glycosides by a general and practical
strategy under mild conditions. The traditional C-
glycosylation
reactions
generally
require
stoichiometric organometallic reagents such as tin,
zinc, lithium, aluminium and Grignard reagents,
which are very sensitive to air and moisture.[1,3] The
de novo synthesis of saccharides using Achmatowicz
rearrangement products as glycosyl donors has
emerged as a powerful tool with excellent regio- and
stereospecific control via Pd-π-allyl intermediate[4]
(Scheme 1a). Many elegant de novo synthesis of
mono- and oligosaccharides have been reported by
O’Doherty and other groups, especially for the N-
glycosylation to access homoadenosine[5]. Most
recently, Tong group disclosed a C-aryl glycosylation
Scheme
1.
Glycosylation
strategies
using
Achmatowicz rearrangement products.
1
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10.1002/adsc.202001136
Advanced Synthesis & Catalysis
for C-alkyl glycosylation by the unique allyl-allyl
coupling process with excellent regio- and
diastereoselectivities (Scheme 1c).
could proceed under very mild conditions, and the
yield could not be further increased under higher
temperature compared to room temperature (Table 1,
entries 17-18). If DABCO was removed from the
reaction conditions, the yield would drop to 20%
(Table 1, entry 19).
Coumarins, as significantly bioactive and
fluorescent
compounds
with
interesting
photophysical properties, are widely utilized as
fluorescent imaging agents, non-linear optical
materials, liquid crystals and so on.[8] When
coumarins are attached to glycosides, the fluorescent
performance and water-solubility would be improved.
Previously, 3-cyano-4-methylcoumarin was used as
allyl nucleophile for asymmetric Michael addition
with good enantioselectivities.[9a] The electron-
withdrawing cyano group at C3 position enhanced the
acidity of γ-H to generate dienolate by in situ
deprotonating. A series of functionalized coumarins
have been prepared using methylcoumarins as allyl
nucleophiles despite the formation of α- or γ-
regioisomers under basic conditions.[9] Basing on our
continuing endeavours on the modifications of
Achmatowicz rearrangement products,[10] herein, we
reported an advanced Pd-catalyzed highly regio- and
Table 1. Optimization of the reaction conditions.[a]
Entry
1
2
Catalyst
Pd(OAc)2 Xantphos THF
PdCl2(PP
h3)2
Ligand
Solvent
Yield[b]
62
55
Xantphos THF
3
4
5
6
7
8
9[c]
10[d]
11[e]
12[f]
13
14
15
16
17[g]
18[h]
19[i]
Pd(PPh3)4 Xantphos THF
Pd(dba)2 Xantphos THF
56
54
71
57
40
< 5
61
42
< 5
< 5
56
33
< 5
< 5
66
64
20
diastereoselective
C-glycosylation
using
Pd(OAc)2 PPh3
Pd(OAc)2 P(OPh)3
Pd(OAc)2 P(C6F5)3
Pd(OAc)2 dppe
Pd(OAc)2 PPh3
Pd(OAc)2 PPh3
Pd(OAc)2 PPh3
Pd(OAc)2 PPh3
Pd(OAc)2 PPh3
Pd(OAc)2 PPh3
Pd(OAc)2 PPh3
Pd(OAc)2 PPh3
Pd(OAc)2 PPh3
Pd(OAc)2 PPh3
Pd(OAc)2 PPh3
THF
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
toluene
MeCN
DMSO
THF
Achmatowicz rearrangement products as donors and
methylcoumarins as acceptors by allyl-allyl coupling
process. It is the first time to achieve the allyl-allyl
coupling reaction between cyclic allyl donors and
allyl acceptors. It provides a simple and efficient
method to access biologically important C-
glycosides with excellent γ-regioselectivities and
high diastereoselectivities. The stereodivergent
enantioselecive synthesis of C-glycosides and
fluorescent investigations further highlight this novel
C-glycosylation reaction.
We began to optimize the C-glycosylation
conditions in Table 1. 3-Cyano-4-methylcoumarin
(1a) and Achmatowicz rearrangement product (2a)
were initially chosen as the model substrates for the
preparation of C-glycosides (3a). The reaction could
proceed smoothly with excellent regioselectivities
and moderate yields using Pd(II) or Pd(0) as catalysts
at room temperature (Table 1, entries 1-4). Pd(OAc)2
was demonstrated to be the most efficient catalyst
(Table 1, entry 1). To our delight, when PPh3 was
used instead of Xantphos, the yield was improved to
71% (Table 1, entry 5). But the performance for other
ligands, such as electron-donating, electron-
withdrawing, and bidentate ligands, was worse than
PPh3 (Table 1, entries 6-8). Both organic and
inorganic bases were screened and DABCO gave the
higher yield (Table 1, entries 9-12). iPr2NEt and NEt3
could promote this transformation albeit the lower
yields, while none of the desired products were
observed using DBU or K2CO3 as base (Table 1,
entries 11 and 12). The solvent effect was very
obvious for this transformation (Table 1, entries 13-
16). The yields dropped dramatically using CH2Cl2 or
toluene as solvent (Table 1, entries 13-14). The
reaction failed to occur in more polar solvents, such
as MeCN and DMSO, may due to the strong
coordination between the solvent and metal catalyst
(Table 1, entries 15-16). Remarkably, the reaction
THF
THF
[a] Conditions: 1a (1.5 equiv), 2a (1.0 equiv), DABCO (1.5
equiv), catalyst (5 mol%), ligand (7.5 mol%), solvent (0.05
M), room temperature for 12 h.
[b] Determined by 1H NMR of the crude mixture with
an internal standard.
[c] iPr2NEt was used instead of DABCO.
[d] NEt3 was used instead of DABCO.
[e] DBU was used instead of DABCO.
[f] K2CO3 was used instead of DABCO.
[g] The reaction was conducted at 40
[h] The reaction was conducted at 60
℃
℃
.
.
[i] The reaction was conducted without DABCO.
With the optimized conditions in hand, we
explored the substrate scope of the Pd-catalyzed C-
glycosylation reaction at room temperature in Table 2.
Various methylcoumarins
1
and Achmatowicz
rearrangement products 2 were used as substrates to
afford C-glycosides 3 in good yields (up to 74%) with
excellent γ-regioselectivities (more than 20:1) and
diastereoselectivities (more than 20:1). Both electron-
rich and electron-deficient methylcoumarins could
provide C-glycosides (3a-3f) without obviously
electronic effect. The yield for 7-methyl product (3f)
was slightly lower than others. If acetate (2a’) or
2
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10.1002/adsc.202001136
Advanced Synthesis & Catalysis
pivalate (2a”) was used as leaving groups rather than
tert-butylcarbonate (2a), the yields of 3a decreased
dramatically. To access full control the
diastereoselectivities of C-glycosides, both cis-2 and
trans-2 were prepared and isolated with excellent dr
(more than 20:1) as starting materials. A series of cis-
disubstituted dihydropranones were acquired in
excellent diastereoselectivities (3g-3m) from cis-2.
The yields for methyl, ethyl and n-propyl substituted
products (3g-3i) were higher than i-propyl,
cyclopropyl and cyclopentyl ones (3j-3l), and the
yield of ethyl product (3h) was obviously higher
compared to others, which may hint the steric
hindrance of dihydropranones could influence the
yields. The electron-withdrawing 6-choro coumarin
could be well tolerated in this transformation to
supply 3m in 67% yield. When trans-2 were used as
substrates,
kinds
of
trans-disubstituted
dihydropranones were obtained in excellent
diastereoselectivities (3n-3t). As the substituted
groups for Achmatowicz rearrangement products
changed from methyl, ethyl and n-propyl to i-propyl,
cyclopropyl and cyclopentyl, the similar trend was
also observed for trans-products (3n-3s). The yield
for trans-ethyl product (3o) was higher than others.
Encouragingly, 3t was acquired in 71% yield for
electron-donating 7-methyl coumarin. Therefore, the
diastereoselectivities of C-glycosides 3 were totally
determined by the stereo-configuration of
Achmatowicz rearrangement products 2.
Subsequently,
the
stereodivergent
and
diastereoselevtive applications of C-glycosylation
reactions were investigated in Scheme 2. The
enantioenriched
Achmatowicz
rearrangement
Table 2. Substrate scope of the C-glycosylation.[a,b]
products cis-4a, trans-4a’, cis-4b and trans-4b’ were
prepared by asymmetric reduction of 2-acetylfuran
using chiral (R,R)-TsDPEN and (S,S)-TsDPEN
respectively. The stereospecific α- and β-glycosidic
bonds were formed in cis-5a, trans-5a’, cis-5b and
trans-5b’ (Scheme 2a). The stereoselectivities of C-
glycosides can be well diversified by the control of
chiral ligands and substrates. Benzyl mercaptan, as
another thiol nucleophile, could site-selectively attack
the olefin of dihydropyranone 3j to afford tetrahydro-
β-pyrone 6a in high regio- and diastereoselectivity
(Scheme 2b). The pseudoaxially oriented substituents
at C2’ and C6’ positions of Achmatowicz
rearrangement product 3j supply enough steric
hindrance to enforce the equatorial approach of
nucleophile, which led to the excellent
diastereoselevtivity in this 1,4-addition.[10a]
[a]
Reaction conditions: 1 (1.5 equiv), 2 (1.0 equiv),
Pd(OAc)2 (5 mol %), PPh3 (7.5 mol %), DABCO (1.5
equiv), THF (0.05 M), rt for 12-24 h.
[b] Yield of isolated product.
[c] 2a’ was used instead of 2a.
[d] 2a’’ was used instead of 2a.
[e]
cis-2 was used and single isomer (dr > 20:1) was
determined by 1H NMR analysis.
[f]
trans-2 was used and single isomer (dr > 20:1) was
determined by 1H NMR analysis.
Scheme 2. The stereodivergent and diastereoselevtive
application of C-glycosylation.
3
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10.1002/adsc.202001136
Advanced Synthesis & Catalysis
The Pd-catalyzed C-glycosylation reaction could
result in excellent regio- and diastereoselevtivities
under mild conditions. We considered that the strong
electron-withdrawing “cyano” group in the coumarin
was necessary and crucial for this transformation.
The mechanistic experiments were conducted in
Scheme 3. No reaction occurred in the absence of
cyano group of 1u as substrate. If the 3-cyano-4-
methylcoumarin
was
converted
to
2-
pyridinylcoumarin 7a by Co-catalyzed [2+2+2]
reaction, the C-glycosylation would not proceed
using 7a as substrate (Scheme 3a). Then, an
orthogonal experiment using cis-2g and trans-2g
mixed in 1:1 ratio was conducted under standard
conditions. 3g and 3n were obtained in 62% and 58%
yield respectively without any epimerization
observed (Scheme 3b).
Scheme 4. Proposed mechanism for Pd-catalyzed C-
glycosylation.
Coumarins are well-known donor parts of
fluorescent dyes due to their chemical stability,
photostability, and large Stokes shifts. The cyano
group in C3 position of coumarins further improve
the fluorescence intensity, fluorescence quantum
yields, and promote the fluorescence emission
wavelength red-shifted.[11] We investigated the
fluorescent performance of glycosyl coumarins 3 and
found the coincident phenomena for C-glycosides 3b
and 3e in Figure 1.[12] The λex and λem shifted to
longer wavelengths in three different solvents (CHCl3,
EtOH and DMSO). Notably, the λem was up to 484
nm in DMSO for 3b. The fluorescence quantum
yields were also improved for 3b (Φ = 0.92 in EtOH)
and 3e (Φ = 0.62 in EtOH), which revealed the C-
glycosides 3 could be potentially employed as novel
fluorescent materials for bioimaging and biosensing.
Scheme 3. Mechanistic experiments for C-glycosylation
According to the mechanistic experiments above,
we have proposed the mechanism in Scheme 4. Pd(II)
is initially reduced by PPh3 to generate Pd(0), which
would coordinate with the olefin of Achmatowicz
rearrangement products (cis-2) from less-hindered
bottom face to yield intermediate A. Then, π-allyl-Pd
intermediate B is formed by an oxidative addition-
decarboxylation sequence. The nucleophilic addition
of dienolate D to π-allyl-Pd intermediate B occurs to
give intermediate C in high regioselectivities by allyl-
allyl coupling process. The γ-position of
methylcoumarin 1 is more nucleophilic than α-
position due to the electronic and steric effect of
cyano group at C3 position.[9] Therefore, desired C-
glycosides 3 are acquired instead of 3’. In addition, the
cope rearrangement of 3 is severely inhibited under mild
conditions.
Figure 1. [a] Excitation and emission spectra of 3b (0.65
μM in each solvent). [b] Excitation and emission spectra of
3e (0.62 μM in each solvent).
In summary, we have developed a Pd-catalyzed C-
glycosylation by a unique allyl-allyl coupling process
using Achmatowicz rearrangement products as
donors and methylcoumarins as acceptors under mild
conditions. It provides a general and practical route to
access biologically important C-glycosides with
excellent regioselectivities and diastereoselectivities.
The stereodivergent enantioselecive synthesis of C-
glycosides further highlights this method. Beyond
this research, we have investigated the fluorescent
performance of coumarin-glycosides, which showed
4
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10.1002/adsc.202001136
Advanced Synthesis & Catalysis
excellent fluorescence quantum yields with red-
shifted emission wavelengths. The further biological
evaluations and optical applications (in vitro and in
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Representative procedures for the synthesis of C-
glycosides (3): To a mixture of Pd(OAc)2 (0.01 mmol),
PPh3 (0.015 mmol), DABCO (0.3 mmol) in THF (4 mL),
tert-butyl(5-oxo-5,6-dihydro-2H-pyran-2-yl)carbonate (0.2
mmol) and 4-methyl-2-oxo-2H-chromene-3-carbonitrile
(0.3 mmol) were added. The mixture was stirred at room
temperature for 12h. Then the reaction mixture was filtered,
evaporated under reduced pressure and purified by column
chromatography (petroleum ether: EtOAc = 1:1) to give 3a
(35 mg, 63% yield) as a white solid.
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Acknowledgements
This work was supported by grants from the National Natural
Science Foundation of China (21702025, 51703018, 21978039),
Science and Technology Innovation Foundation of Dalian City
(2019J12GX029), the Fundamental Research Funds for the
Central Universities (DUT20YG120, DUT19LK60).
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Dong, Y. Zheng, J. Org. Chem. 2018, 83, 12822-12830; b)
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Y. B. Zheng, Heterocycles 2018, 96, 1779-1785; c) W.
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[12] For more details about the fluorescent performance
of coumarin-glycosides, please see the supporting
information.
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5
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Advanced Synthesis & Catalysis
UPDATE
Palladium-Catalyzed Regio- and Diastereoselective
C-Glycosylation by Allyl-Allyl Coupling
Adv. Synth. Catal. Year, Volume, Page – Page
Junhao Li, Nan Zheng,* Xuelun Duan, Rui Li,
Wangze Song*
6
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