Total synthesis of triazole-linked C-glycosyl flavonoids in alternative solvents and environmental assessment in terms of reaction, workup and purification

Article abstract of DOI:10.1039/c6gc01647b

An efficient total synthesis of triazole-linked C-glycosyl flavonoids was developed without the use of protective groups in order to promote atom economy, employing alternative solvents, and choosing the least toxic reagents. Aiming to measure the impact of the operation that affects the mass intensity to a greater extent, we envisaged first determining this green metric for the reaction (MI_R), the workup (MI_W), and the purification (MI_P) for each step and then taking advantage of these values to calculate the contributions to the total synthesis.

Full text of DOI:10.1039/c6gc01647b

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Total synthesis of triazole-linked C-glycosyl
flavonoids in alternative solvents and
environmental assessment in terms of reaction,
workup and purification†
Cite this: DOI: 10.1039/c6gc01647b
Freddy Pessel, Isabelle Billault and Marie-Christine Scherrmann*
An efficient total synthesis of triazole-linked C-glycosyl flavonoids was developed without the use of pro-
tective groups in order to promote atom economy, employing alternative solvents, and choosing the least
toxic reagents. Aiming to measure the impact of the operation that affects the mass intensity to a greater
extent, we envisaged first determining this green metric for the reaction (MIR), the workup (MIW), and the
purification (MIP) for each step and then taking advantage of these values to calculate the contributions to
the total synthesis.
Received 16th June 2016,
Accepted 18th July 2016
DOI: 10.1039/c6gc01647b
www.rsc.org/greenchem
Introduction
Flavonoids are natural polyphenols largely present in fruits
and vegetables and most of them are endowed with anti-
oxidant properties.1 The addition of a sugar moiety to these
compounds may increase their bioavailability by enhancement
of their water solubility so that flavonoid-sugars constitute inter-
esting targets with various prospective applications. Indeed,
numerous studies have been dedicated to the synthesis of
flavonoid glycosides.2 Various strategies have been developed
to prepare flavonoid O-glycosides,2,3 C-glycosides,2b,4 or mixed
O,C-glycosides.2 Other kinds of linkages have also been pro-
posed to connect the flavones and the carbohydrate as, for
instance, unsaturated carbon bridge,5 or triazole.6 In the latter
approach, the copper(I) catalysed azide–alkyne cycloaddition
reaction7 was employed for the chemical ligation of propargy-
lated isoflavones6a or perbenzylated flavonol6b and the alkyl
azide containing 2,3-unsaturated pyranoside moiety6a or
deoxy-azido sugars6b (Fig. 1). In both cases, the suitably pro-
tected azide-functionalised carbohydrate was obtained
through a large number of steps, and the protecting groups
were not removed after the cycloaddition.
Fig. 1 Chemical structures of previously reported triazole-linked
flavonoid-sugars.6
oxidant activity of flavonoids by trapping radicals has been
extensively studied and these studies have shown, in particular,
that the hydroxyl functions at positions 3 and 5, associated with
the carbonyl in position 4, induce maximum efficiency.8
In this context, our project aimed at developing an environ-
mentally friendly method for the synthesis of a new class of
molecules in which the structural elements necessary for the
antioxidant activity are maintained1 and a hydrolytically stable
C-glycoside unit is linked by a 1,2,3-triazole ring. The anti-
These results therefore guided us in choosing to introduce
the sugar unit at position 7 of the flavonoid backbone (Fig. 2).
As our synthetic strategy was guided by the principles of
green chemistry9 and more particularly on the non-use of pro-
tective groups in order to promote atom economy, we decided
to employ the ketone 7 (Scheme 1) since, as shown by previous
work carried out in our research institute, this compound can
be prepared in a single step directly from D-glucose.10 In
addition, the ketone function of the C-glycoside gave scope for
the easy introduction of halogen in its alpha position.
Université Paris Sud, ICMMO, UMR CNRS 8182, Bâtiment 420, 91405 Orsay,
France. E-mail: marie-christine.scherrmann@u-psud.fr
†Electronic supplementary information (ESI) available: 1H and 13C spectra for
all compounds; and details of the calculations. See DOI: 10.1039/c6gc01647b
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step and for the whole process of a total convergent synthesis
(PMI).20 This tool allows evaluating the relative proportions
due to the substrates and reagents, the solvents, and the
aqueous phases in the PMI. We propose a complementary
approach to highlight the operation that affects to a greater
extent the mass intensity and calculated, for each step, the
mass intensity for the reaction (MIR), the workup (MIW), and
the purification (MIP):
total mass used for the reaction
Fig. 2 Chemical structures of the target triazole-linked C-glycosyl
flavonoids.
MIR ¼
mproduct
total mass used for the workup
MIW
¼
mproduct
To satisfy the principles of green chemistry, we have also
favoured the use of alternative solvents, i.e. non-toxic or bio-
based, and we have chosen the least toxic reagents. Further-
more, each step as well as the total synthesis of the various
molecules were assessed using the atom economy (AE),11 and
the mass intensity (MI),12,13 or its counterpart, the global
material economy (GME),14 that considers all the materials
used in the process, the mass intensity being connected to the
Sheldon environmental factor E:15
total mass used for the purification
MIP ¼
mproduct
Obviously, the mass intensity MI is the sum of MIR, MIW
and MIP. The related metrics, PMIR, PMIW and PMIP were also
calculated for each branch as well as for the total synthesis of
1a and 1b.
νproductMWðProductÞ
P
AE ¼
Results and discussion
Synthesis of the flavonol moieties
νrMWðrÞ
where MW(r) is the molecular weight of each reactant and νr is
the corresponding stoichiometric coefficient.
The synthesis of compound 3 was described using propargyl
iodide prepared in situ from propargyl bromide and KI21 or
directly propargyl bromide,22 in acetone with K2CO3 as the
base. Although the use of p-toluenesulfonate as the leaving
group is less favourable to the atom economy compared to the
use of propargyl bromide (44% vs. 56%), we decided to use
propargyl p-toluenesulfonate since this reagent is less toxic
1
total mass used in the process
MI ¼
¼
GME
mproduct
mass of waste
E ¼
¼ MI ꢀ 1
mproduct
These metrics are increasingly used to evaluate previously than propargyl bromide. Furthermore, amongst the alterna-
described syntheses,16 or more rarely as tools for comparison tives to organic solvents, polyethylene glycol dimethyl ether
and decision in the syntheses in one17 or more steps.18
(PEG(OMe)2) was chosen since it is known to promote nucleo-
The process mass intensity was chosen by the American philic substitution and because this linear polymer, available
Chemical Society Green Chemistry Institute’s Pharmaceutical in a wide range of molecular weights, is non-volatile, has low
Roundtable as a high-level metric for evaluating processes19 toxicity and high chemical and thermal stability.23 Therefore,
and a tool was proposed to evaluate MI for each individual we carried out the reaction in PEG250(OMe)2 in the presence of
Scheme 1 Synthesis of triazole-linked C-glycosyl flavonoids 1a and 1b from D-glucose and 2’,4’-dihydroxyacetophenone.
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K2CO3. The use of non-volatile solvents usually requires extrac- (>8%). Alternatively, pyrrolidine was used in the presence of
tion steps. Regarding PEG, its solubility properties imply that acetic acid in a benzene–diethyl ether mixture for the synthesis
the products are generally extracted with Et2O. Compound 3 of didehydroparadols from vanillin26 or, in diethyl ether or
was thus isolated in 83% yield by extraction with this solvent THF, for the preparation of diarylheptanoids from different
and purified by recrystallization in EtOH. The mass intensity hydroxybenzaldehydes.27 Since the use of such solvents must
for the reaction was relatively low (6.2) but the workup (extrac- be banned, we exploited a pyrrolidine–AcOH mixture for the
tion) was problematic since a large amount of Et2O, a highly condensation between 2′-hydroxy-4′-propargyloxyacetophenone
hazardous solvent, was necessary to extract the product from (3) and 4-hydroxybenzaldehyde, or vanillin, in ethanol or
PEG250(OMe)2 (Table 1).
without solvent, which allowed obtaining a mixture of chal-
This step was optimized and finally, a protocol allowing the cones 5 and flavanones 5′ (Scheme 2). Indeed, ortho-hydroxy-
precipitation of the propargylated compound in acidic chalcones are known to give rise to an isomerism that can be
aqueous medium was found, thus avoiding the use of Et2O controlled by the pH, the cyclic flavanone being favoured
and leading to the decrease of MIW from 28.51 to 8.16 (Table 1 at pH below ∼10 and the chalcone predominating above
and Fig. 3).
pH ∼ 13.28
The reaction without solvent required 5 equiv. of pyrroli-
The next reaction was an aldol condensation enabling the
synthesis of chalcones 5. These compounds are conventionally dine–AcOH instead of only 1 equiv. in EtOH but was faster,
obtained in basic medium after protection of the phenol func- took place at a lower temperature and afforded the E-config-
tional groups.24 These additional protection–deprotection ured chalcones in better yields and lower MIR (Table 2). After
steps are necessary to maintain sufficient electrophilicity of optimizing the reaction conditions, treatment and purification
the aldehyde function but have an impact on the mass inten- were redesigned to decrease the amount of material used.
sity of the reaction sequence; that is why the principles of Initially, these operations were carried out by liquid–liquid
green chemistry recommend avoiding these steps. The aldoli- extraction, washing (NaCl, NaHSO3) and chromatography,
sation reaction can also be carried out in acidic medium,25 but which led to high values of MIW and MIP (Table 2).
in our case, these conditions only led to low conversions
We found that the compounds could be purified by crystal-
lization (EtOH–H2O), which significantly reduced these values
but also allowed using only water, and AcOEt and EtOH, bio-
based solvents for these operations (Fig. 4).
Table 1 Comparison of isolated yields and mass intensities depending
on the workup for isolation of 3 after its synthesis in PEG250(OMe)2 as
the solvent
The most straightforward method to prepare 3-hydroxy-
flavones from chalcones is the Algar–Flynn–Oyamada (AFO)
reaction.29 This base-induced oxidative cyclisation of chalcones
occurs in the presence of hydrogen peroxide and sodium
hydroxide through a mechanism still debated30 and affords
the flavonol, and often an aurone, so that yields are generally
low.31 Therefore, some modifications of the conventional AFO
reaction conditions have been proposed.32 Among the
different protocols tested, the best results were obtained by
treating chalcones 5 suspended in an aqueous solution of
sodium hydroxide by a 30% hydrogen peroxide solution at
Workup by
Yield (%)
MIR
MIW
MIP
MI
Extraction (Et2O)
Precipitation (HCl aq.)
83
82
6.23
6.19
28.51
8.16
5.58
4.96
40.33
19.31
Fig. 3 Amount and nature of reactants and auxiliaries for the synthesis
of 3 (g gproduct−1) for the reaction (MIR), the workup (MIW) and the purifi-
cation (MIP).
Scheme 2 Synthesis of chalcones 5a and 5b and isomerism with
flavanone 5’a or 5’b.
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Table 2 Comparison of isolated yields and mass intensities for the synthesis of 5a and 5b in EtOH or without solvent
Aldehyde
Solvent
EtOHa
Temp., time
Yield (%)
MIR
MIW
MIP
MI
4a
4a
4a
4b
4b
4b
60 °C, 24 h
30 °C, 2 h
30 °C, 2 h
60 °C, 24 h
30 °C, 6 h
30 °C, 6 h
80c
84c
84d
68c
80c
71d
10.8
3.9
3.9
11.7
3.8
4.3
110.3
82.3
54.6
118.2
143.7
57.7
1010.6
965.0
11.7
1222.6
828.0
49.5
1131.7
1051
70.2
1352.5
975.6
111.6
b
—
b
—
EtOHa
b
—
b
—
a 1 equiv. pyrrolidine–AcOH. b 5 equiv. pyrrolidine–AcOH. c Purification by chromatography. d Purification by crystallization.
in ethyl acetate led to the use of large volumes of this solvent
(Table 3). We then opted for solid–liquid extraction to recover
pure compounds.
This new protocol has proved effective since flavonol 6a was
recovered in a similar yield (65%) and 6b in a greater yield
(64%) compared with liquid–liquid extraction (Table 3). In
addition, the MIP were divided by about 5.5 (6a) and 7.9 (6b)
which has resulted in greatly reducing the mass intensities
(Table 3 and Fig. 6).
Evaluation of whole sequences for the syntheses of 6a and 6b
PMIR, PMIW and PMIP of the linear sequence (2 → 6,
Fig. 7) can be calculated from the mass intensities, the
Fig. 4 Amount and nature of reactants and auxiliaries for the synthesis
of 5, 5’a (g gproduct−1) for the reaction (MIR), the workup (MIW) and the
purification (MIP). For 5, 5’b, see ESI.†
Table 3 Comparison of isolated yields and mass intensities for the
purification of flavonols 6a and 6b by liquid–liquid extraction (LLE) or
solid–liquid extraction (SLE)
room temperature. A meticulous analysis of all the products of
the reaction has shown that the benzoic acids 10 and 11a or
11b were formed up to approximately 16% with flavonol 6a or
6b respectively (Fig. 5).
Formation of these by-products can be explained by the oxi-
dation of 3-hydroxyflavones formed through a mechanism
similar to that of the oxygenolysis of these compounds in
basic medium.33 Therefore, to separate flavonols and the acid
10 that precipitate together during the acidification of the reac-
tion medium, while 11 remained in solution, we realized a
liquid–liquid extraction (EtOAc–NaHCO3 aq.). The mass inten-
sity increased significantly since the low solubility of flavonols
Flavonol
Purification
Yield (%)
MIR
MIW
MIP
MI
726.8
214.3
1025.2
222.2
6a
LLE
SLE
LLE
SLE
65
65
61
64
18.4
18.4
24.7
23.5
81.9
81.9
87.1
82.7
626.5
113.9
913.3
116.0
6b
Fig. 6 Amount and nature of reactants and auxiliaries for the synthesis
of 6a (g gproduct−1) for the reaction (MIR), the workup (MIW) and the
purification (MIP). For 6b, see ESI.†
Fig. 5 Structures of 3-hydroxyflavone 6a or 6b and of by-products 10,
11a and 11b.
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Fig. 7 Synthesis of 6 through a linear three-step sequence, each step i
occurring in a yield of εi and a mass intensity MI(i).
yields of each step and the molecular weights MW of the
compounds:
ꢀ
ꢀ
ꢁ
MWð3Þ
ε2ε3MWð6Þ
MWð5Þ
PMI2R!6
¼
MIðR1Þ ꢀ 1
ꢁ
Fig. 8 Composition by mass of the material used for the synthesis of
6a (g gproduct−1) for the reaction (PMIR), the workup (PMIW) and the
purification (PMIP). For 6b see ESI.†
þ
MIðR2Þ ꢀ 1 þ MIðR3Þ
ε3MWð6Þ
MWð3Þ
MWð5Þ
PMI2W!6
PMI2P!6
¼
¼
MIðW1Þ þ
MIðW2Þ þ MIðW3Þ
ε2ε3MWð6Þ
ε3MWð6Þ
since it could not be purified by other techniques. This led to
a very high mass intensity (Table 5 and Fig. 10), which was
lower with method B, therefore the latter method was adopted
for the total synthesis.
MWð3Þ
MWð5Þ
MIðP1Þ þ
MIðP2Þ þ MIðP3Þ
ε2ε3MWð6Þ
ε3MWð6Þ
PMI2!6 ¼ PMIR2!6 þ PMIW2!6 þ PMI2P!6
Evaluation of whole sequences for the syntheses of 8
As shown by this analysis (Table 4), the global mass intensi-
ties were 336.44 for 6a and 409.84 for 6b, PMIR accounting for
only 8% in both cases (Fig. 8).
The global atom economy of the synthesis of 8 from D-glucose
was 57% and the global yield was 54%. The PMI were calcu-
Synthesis of the sugar moiety
The first step in this sequence was Lubineau’s reaction10 involv-
ing a Knoevenagel condensation34 between the unprotected
D-glucose and pentanedione in an aqueous medium. This quan-
titative reaction, whose by-products are sodium acetate, CO2 and
H2O, has an atom economy of 60%. Using more concentrated
conditions with respect to the original process, and optimizing
the workup, we obtained a mass intensity of 24.52 (Fig. 9).
We recently described35 a modification of the original syn-
thesis of the bromo derivatives 8 36 by using L-proline and Br2
in EtOH. We envisaged replacing bromine, a reagent with
acute toxicity (categories 1, 2, 3), by polymer-bound pyridinium
tribromide, whose toxicity is lower. Although the use of the
supported-reactive allowed avoiding treatment with sodium
bisulfite since the brominating agent was removed from the
medium by simple filtration, MIW was higher mainly due to
the volume of ethanol required to wash the resin (Table 5).
The recovery of compound 8 in a pure form was crucial for
the success of the next synthetic step. Unfortunately, using
both methods, chromatography was necessary to isolate 8
Fig. 9 Amount and nature of reactants and auxiliaries for the synthesis
of 7 (g gproduct−1) for the reaction (MIR), the workup (MIW) and the purifi-
cation (MIP).
Table 4 Yields and green metrics for each step of the synthesis of 6a and 6b and for the whole sequence
Step
2 → 3
3 → 5a
3 → 5b
5a → 6a
5b → 6b
2 → 6a
2 → 6b
AE (%)
Yield (%)
MIR
MIW
MIP
44
82
6.18
8.16
4.96
19.31
18.31
94
84
3.90
54.60
11.72
70.23
69.23
94
71
4.33
57.69
49.52
111.55
110.55
85
65
18.38
81.96
113.97
214.32
213.32
86
64
23.49
82.72
116.01
222.23
221.23
49
45
28.48
171.21
136.75
336.44
335.44
52
37
34.87
178.91
196.05
409.84
408.84
MI
E
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Table 5 Comparison of isolated yields and mass intensities for the syn-
thesis of 8 using Br2 (method A) or polymer-bound pyridinium tri-
bromide (method B)
theless be lowered by recycling the solvent used for the chrom-
atography but to the detriment of higher energy expenditure
(Fig. 11).
Yield
(%)
Synthesis of the triazole-linked C-glycosyl flavonoids 1a and 1b
Method
MIR
MIW
MIP
MI
PEG2000 proved to be an excellent solvent for carrying out, in a
one-pot procedure, the nucleophilic substitution of bromine
derivatives by sodium azide and the copper-catalyzed azide–
alkyne 1,3-dipolar cycloaddition.35 We applied this method for
the synthesis of triazole-linked flavonoid-sugars 1a and 1b
(Fig. 1, R = H or OMe respectively). CuI or the CuSO4/Na ascor-
bate catalytic system was investigated as the Cu(I) source
(Table 6).
A (Br2)
B (polymer bound
reagent)
61
54
13.11
5.03 1775.19 1793.34
16.11 19.76 1190.70 1226.57
The two catalyst systems have been found effective in this
transformation, the CuSO4/Na ascorbate system giving slightly
better results in terms of yield but also lower mass intensities.
As in most of the preceding steps, the major part of the mass
required for the preparation of 1a or 1b was not used for carry-
ing out the reaction but for treatment. This was achieved by
simple operations of precipitation and washings and afforded
pure 1a or 1b without the need of further purification, allow-
ing for MIP = 0 in all cases (Table 6).
Evaluation of whole sequences for the syntheses of 1a and 1b
1a and 1b were obtained from D-glucose and 2′,4′-dihydroxy-
acetophenone via convergent syntheses with two parallel
sequences and one point of convergence. The global atom
economies (GAE), the global reaction mass efficiencies
(GRME), i.e. the percentage of the mass of the reactants that
Fig. 10 Amount and nature of reactants and auxiliaries for the synthesis
of 8 (g gproduct−1) for the reaction (MIR), the workup (MIW) and the purifi-
cation (MIP).
lated from the molecular weights MW, the yields of the second
step (ε′2) and the mass intensities M(1) and M(2) of the two
steps:
ꢀ
ꢁ
MWð7Þ
PMIgRlc!8
¼
MIðR1′Þ ꢀ 1 þ MIðR2′Þ
ε′2MWð8Þ
Fig. 11 Composition by mass of the material used for the synthesis of 8
(g gproduct−1) for the reaction (PMIR), the workup (PMIW) and the purifi-
cation (PMIP).
MWð7Þ
PMIgWlc!8
PMIgPlc!8
¼
¼
MIðW1′Þ þ MIðW2′Þ
ε′2MWð8Þ
MWð7Þ
MIðP1′Þ þ MIðP2′Þ
ε′2MWð8Þ
Table 6 Yields and mass intensities for the one pot SN-CuAAC between
8 and 6a or 6b using CuSO4/NaAsc or CuI as catalysts in PEG2000–H2O
(3.3/1) at 60 °C
PMIglc!8 ¼ PMIRglc!8 þ PMIWglc!8 þ PMIgPlc!8
As expected from the large value of MIP for the bromination
step, the PMI for the two-step synthesis of 8 from D-glucose
was very high (1258.36) with most of the mass used for the
purification in the second step, showing that chromatography
should be avoided if possible. This high value should never-
Flavonol Catalyst
Yield (%) MIR MIW
5.87 202.72
MIP MI
6a
6b
CuSO4–NaAsc 91
CuI 88
CuSO4–NaAsc 90
CuI 85
0
0
0
0
208.60
6.30 210.23
5.94 212.86
6.38 224.06
216.53
218.80
230.45
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remains in the product taking into account the experimental
conditions (excess of reagents and yields), and the global mass
Experimental
a
previously 1H and 13C NMR spectra were recorded on Bruker spec-
intensities (PMITS
)
were calculated using
described algorithm14 (Table 7). Furthermore, we also calcu- trometers. Chemical shifts (δ) in ppm, are given relative to
lated the PMI for the reactions (PMITRS), the workups (PMITWS
and the purifications (PMIPTS) using the following equations:
)
tetramethylsilane for 1H NMR and relative to the CD3OD or d6-
DMSO resonances at 49.00 and 39.52 ppm, respectively for
13C NMR. Signals were assigned on the basis of H–1H COSY,
1
m8
PMITRS
¼
ðPMIðRglc!8Þ ꢀ 1Þ
ðPMIðR2!6Þ ꢀ 1Þ þ PMIRð6þ8!1Þ
HSQC and HMBC experiments. HRMS spectra were recorded
in positive or negative mode with a microtof-QII spectrometer
(Bruker) using electrospray ionization. IR spectra were
recorded on an FT/IR Jasco 4100 equipped with diamond ATR.
Elemental analyses were performed at the service central de
microanalyses du CNRS at Gif-sur-Yvette, France.
m1
m6
þ
m1
m8
m1
m6
m1
PMITWS
¼
¼
PMIðWglc!8Þ þ
PMIðW2!6Þ þ PMIWð6þ8!1Þ
2′-Hydroxy-4′-propargyloxyacetophenone (3)
m8
m1
m6
m1
2′,4′-Dihydroxyacetophenone (10.551 g, 69.34 mmol) was dis-
solved in PEG250 (35 mL) and heated at 60 °C. K2CO3 in the
powder form (5.751 g, 41.61 mmol) was slowly added and the
mixture was stirred for 15 min. Propargyl p-toluenesulfonate
(12.0 mL, 69.34 mmol) was added and the mixture was stirred
at 60 °C for 2 days. Water (70 mL) and HCl 37% (7 mL) were
added and the crude product precipitated upon cooling. The
product was collected by filtration and washed with water
(10 mL). The crude product was recrystallized with ethanol
96% (31 mL). Crystals were collected by filtration and washed
with cold ethanol 96% (20 mL). The filtrate was concentrated
and a second recrystallization with ethanol 96% (7.0 mL)
afforded crystals that were collected by filtration and washed
with cold ethanol 96% (10 mL). The two crops afforded 3 as
white needles (10.816 g, 56.9 mmol, 82%); m.p. 71–73 °C,
EtOH 96% (lit. 102–103 °C, EtOH;21 65 °C, ligroin;22a
71.2–71.5 °C, AcOEt).22h Spectral data were in accordance with
those previously reported. Elemental analysis: calculated for
C11H10O3: C 69.46%, H 5.30%, O 25.24%. Found: C 69.40%, H
5.28%, O 25.28%.
PMITPS
PMIðPglc!8Þ þ
PMIðP2!6Þ þ PMIPð6þ8!1Þ
m6 and m8 are the masses of 6a or 6b and 8 used in the final
step to get a mass m1 of 1a or 1b.
GRME and GME are directly proportional to the atom
economy, so that the choice of high atom economy reactions
is of high importance. In the case of the total syntheses of 1a
and 1b, AE is, in particular, impacted by the choice of propar-
gyl tosylate as the reactant in the first step of the preparation
of 8 (AE = 44%), choosing a reagent leading to improved atom
economy could be done to the detriment of toxicology con-
siderations. The yield of the reactions and the excess of the
reactants greatly affect GRME and GME. This latter metric is
also very dependent on auxiliaries used (solvents, aqueous
phases for washing, chromatography supports, drying agents,
etc.). For the synthesis of triazole-linked flavonoid-sugars, the
values of GRME indicate that 18 and 14% of the reactant mass
ends up in the final products 1a and 1b respectively. When the
process is considered as a whole, only 0.083 (1a) and 0.066%
(1b) of the total mass used is incorporated into the product as
indicated by the GME values. The total mass (PMITS) is used to
(i) implement the reactions (PMITRS, 3%), (ii) carry out the
General procedure for synthesis of chalcone–flavanone 5, 5′
Acetic acid (1.5 mL, 26.2 mmol) was added to pyrrolidine
(2.15 mL, 26.2 mmol) cooled with a bath of ice and water.
After a few minutes, the mixture was warmed at 30 °C. Then,
compound 3 finely ground (997.7 mg, 5.25 mmol) and hydro-
xybenzaldehyde (4-hydroxybenzaldehyde (4a) or vanillin (4b)
(5.25 mmol)) were added. The mixture was stirred at 30 °C for
2 h (4a) or 6 h (4b).
workup (PMITWS, 44%) and (iii) purify the compounds (PMITPS
48%).
,
Table 7 Yields and green metrics for the total syntheses of 1a and 1b
Product
1a
1b
2′,4-Dihydroxy-4′-propargyloxychalcone (5a) and 4′-hydroxy-
7-propargyloxyflavanone (5′a). After cooling at r.t., ethyl acetate
(20 mL) and a solution of NaCl 12% (12 mL) were added. The
aqueous layer was extracted with ethyl acetate (2 × 10 mL). The
organic layers were combined, washed with NaClsat (15 mL),
NaHSO3sat (15 mL, vigorous stirring for 4 h) and NaClsat
(15 mL). The organic layer was dried over MgSO4 (3 g) and con-
centrated in vacuo. The crude product was purified by silica gel
column chromatography (cyclohexane–acetone 8 : 2 then 7 : 3)
to give 5a–5′a (1.0 : 0.5) as a solid (1.30 g, 84%) or by crystalliza-
tion: after dissolution in hot ethanol 96% (3.5 mL), water
(2 mL) was added and the mixture 5a–5′a precipitated upon
GAE (%)
47
45
41
18
48
32
33
14
Yield from D-glucose (%)
Yield from 2 (%)
GRME (%)
PMITRS (% of MITS
PMITWS (% of MITS
PMITPS (% of MITS
PMITS
)
)
)
35.46 (3%)
44.54 (3%)
333.70 (28%)
836.93 (69%)
363.38 (24%)
1111.55 (73%)
1206.10a
0.083
1519.48a
0.066
GME (= 1/PMITS) (%)
a PMITS values were systematically calculated according to the method
previously described14 or by addition of PMITRS, PMIWTS, and PMITPS
Both methods gave strictly the same results allowing the checking of
the data.
.
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cooling. The product was collected by filtration and washed 7.77 (d, Jα,β = 15.0 Hz, 1 H, H-α), 7.83 (d, Jα,β = 15.0 Hz, 1 H, H-
with cold ethanol 96% (5 mL). The filtrate was concentrated β), 8.31 (d, J5′,6′ = 9.0 Hz, 1 H, H-6′), 9.75 (s, 1 H, 4-OH), 13.62
and a second precipitation with ethanol 96% (2.0 ml) and (s, 1 H, 2′-OH); 5′b: 2.68 (dd, J2,3a = 3.0 Hz, J3a,3b = 17.0 Hz,
water (1 mL) afforded a product that was collected by filtration 1 H, H-3a), 3.25 (dd, J2,3b = 13.0 Hz, J3a,3b = 17.0 Hz, 1 H,
and washed with cold ethanol 96% (5 mL). The two crops H-3b), 3.63 (t, JHCuC,HCuC–CH = 2.5 Hz, 1 H, HCuC), 3.79 (s,
2
afforded 5a–5′a as a solid (1.30 g, 84%); νmax (neat)/cm−1 1671 3 H, 3′-OCH3), 4.89 (d, JHCuC,HCuC–CH = 2.5 Hz, 2 H, HCuC–
2
(νCvO), 3208 (νOH), 3288 (νuC–H); δH (360 MHz, d6-DMSO), 5a: 3.65 CH2), 5.50 (dd, J2,3a = 3.0 Hz, J2,3b = 13.0 Hz, 1 H, H-2), 6.67 (d,
(t, JHCuC,HCuC–CH = 2.5 Hz, 1 H, HCuC), 4.92 (d, JHCuC,HCuC–CH
J6,8 = 2.5 Hz, 1 H, H-8), 6.69 (dd, J6,8 = 2.5 Hz, J5,6 = 8.5 Hz, 1 H,
= 2.5 Hz, 2 H, HCuC–CH2), 6.56 (d, J3′,5′ = 2.5 Hz, 1 H, H-3′), H-6), 6.80 (d, J5′,6′ = 8.0 Hz, 1 H, H-5′), 6.93 (dd, J2′,6′ = 2.0 Hz,
6.60 (dd, J3′,5′ = 2.5 Hz, J5′,6′ = 9.0 Hz, 1 H, H-5′), 6.84 (d, J2,3 J5′,6′ = 8.0 Hz, 1 H, H-6′), 7.13 (d, J2′,6′ = 2.0 Hz, 1 H, H-2′), 7.73
J5,6 = 9.0 Hz, 2 H, H-3 and H-5), 7.77 (d, J2,3 = J5,6 = 9.0 Hz, 2 H, (d, J5,6 = 8.5 Hz, 1 H, H-5), 9.11 (s, 4′-OH); δC (90.6 MHz, d6-
H-2 and H-6), 7.77 (d, Jα,β = 15.5 Hz, 1 H, H-α), 7.81 (d, Jα,β DMSO); 5b: 55.86 (3-OCH3), 55.92 (HCuC–CH2), 78.5 (HCuC),
15.5 Hz, 1 H, H-β), 8.27 (d, J5′,6′ = 9.0 Hz, 1 H, H-6′); 5′a: 2.67 78.9 (HCuC), 102.0 (C-3′), 107.6 (C-5′), 111.8 (C-2), 114.3 (C-1′),
2
2
=
=
(dd, J2,3a = 3.0 Hz, J3a,3b = 17.0 Hz, 1 H, H-3a), 3.20 (dd, J2,3b
=
=
115.6 (C-5), 117.4 (C-α), 124.8 (C-6), 126.1 (C-1), 132.5 (C-6′),
145.4 (C-β), 148.1 (C-3), 150.2 (C-4), 163.5 (C-4′), 165.4 (C-2′),
13.0 Hz, J3a,3b = 17.0 Hz, 1 H, H-3b), 3.62 (t, JHCuC,HCuC–CH
2
2.5 Hz, 1 H, HCuC), 4.88 (d, JHCuC,HCuC–CH = 2.5 Hz, 2 H, 192.0 (CvO); 5′b: 43.2 (C-3), 55.7 (3′-OCH3), 55.9 (HCuC–
2
HCuC–CH2), 5.51 (dd, J2,3a = 3.0 Hz, J2,3b = 13.0 Hz, 1 H, H-2), CH2), 78.5 (HCuC), 78.8 (HCuC), 79.5 (C-2), 102.0 (C-8), 110.3
6.65 (d, J6,8 = 2.5 Hz, 1 H, H-8), 6.69 (dd, J6,8 = 2.5 Hz, J5,6 = 8.5 (C-6), 111.2 (C-2′), 114.9 (C-10), 115.2 (C-5′), 119.7 (C-6′), 128.0
Hz, 1 H, H-6), 6.80 (d, J2′,3′ = J5′,6′ = 8.5 Hz, 2 H, H-3′ and H-5′), (C-5), 129.6 (C-1′), 146.9 (C-4′), 147.6 (C-3′), 163.0 (C-9), 163.4
7.34 (d, J2′,3′ = J3′,5′ = 8.5 Hz, 2 H, H-2′ and H-6′), 7.73 (d, J5,6
=
(C-7), 190.4 (C-4); HRMS (ESI): calculated for [C19H16O5 + H]+:
8.5 Hz,
1
H, H-5); δC (90.6 MHz, d6-DMSO), 5a: 55.9 325.1071. Found: 325.1071. Calculated for: [C19H16O5 + Na]+:
(HCuC–CH2), 78.5 (HCuC), 78.8 (HCuC), 102.0 (C-3′), 107.6 347.0890. Found: 347.0887; Elemental analysis: calculated for
(C-5′), 114.4 (C-1′), 115.9 (C-3 and C-5), 117.3 (C-α), 125.7 (C-1), C19H16O5: C 70.36%, H 4.97%, O 24.66%. Found: C 70.14%,
131.4 (C-2 and C-6), 132.4 (C-6′), 145.0 (C-β), 160.5 (C-4), 163.5 H 5.08%, O 24.84%.
(C-4′), 165.3 (C-2′), 192.0 (CvO); 5′a: 43.1 (C-3), 55.9
4′-Hydroxy-7-propargyloxyflavonol 6a. 8 M NaOH (3.78 mL,
(HCuC–CH2), 78.5 (HCuC), 78.8 (HCuC), 79.3 (C-2), 102.0 30.2 mmol) was added to compounds 5a–5′a (500 mg,
(C-8), 110.2 (C-6), 114.9 (C-10), 115.2 (C-3′ and C-5′), 128.0 1.69 mmol). Then, H2O2 30% (870 μL, 8.52 mmol) was slowly
(C-5), 128.3 (C-2′ and C-6′), 129.1 (C-1′), 157.7 (C-4′), 163.0 added and the reaction mixture was stirred at r.t. for 25 min,
(C-9), 163.4 (C-7), 190.4 (C-4); HRMS (ESI): calculated for the mixture was then cooled in an ice bath and HCl 37%
[C18H14O4 + H]+: 295.0965. Found: 295.0950. Calculated for (2.5 mL) mixed with crushed ice (5 mL) was slowly added.
[C18H14O4 + Na]+: 317.0784. Found: 317.0767.
After precipitation, the mixture was filtered and washed with
4-Hydroxy-3-methoxy-4′-propargyloxychalcone
(5b)
and water (20 mL). The crude product was vigorously stirred with a
4′-hydroxy-3′-methoxy-7-propargyloxyflavanone (5′b). After solution of 1 M NaHCO3 (10 mL). The mixture was centrifuged
cooling at r.t., ethyl acetate (10 mL), acetone (10 mL) and a (5000 rpm, 15 min) and the supernatant removed. The solid
solution of NaCl 12% (12 mL) were added. The aqueous layer was again vigorously stirred with a solution of 1 M NaHCO3
was extracted with ethyl acetate (2 × 10 mL). The organic layers (8 mL) and then centrifuged (5000 rpm, 15 min). The super-
were combined, washed with NaClsat (15 mL), NaHSO3sat natant was removed and the precipitate was suspended in
(15 mL, vigorous stirring for 4 h) and NaClsat (15 mL). The water (20 mL) and filtered and dried in a desiccator to give 6a
organic layer was dried over MgSO4 (3 g) and concentrated as a solid (341 mg, 65%); νmax (neat)/cm−1 1592 (νCvO), 3273
in vacuo. The crude product was purified by silica gel column (νuC–H), 3402 (νOH), 3488 (νH-bonded OH); δH (360 MHz, d6-
chromatography (cyclohexane–acetone 8 : 2 then 7 : 3) to give DMSO) 3.67 (t, JHCuC,HCuC–CH = 2.5 Hz, 1 H, HCuC), 4.99
2
5b–5′b (1.0 : 0.4) as a yellow solid (1.36 g, 80%) or by recrystalli- (d, JHCuC,HCuC–CH = 2.5 Hz, 2 H, HCuC–CH2), 6.94 (d, J2′,3′
zation: the crude product was dissolved in hot ethanol 96% J5′,6′ = 9.0 Hz, 2 H, H-3′ and H-5′), 7.07 (dd, J6,8 = 2.0 Hz, J5,6
(59 mL) and the mixture 5b–5′b precipitated upon cooling. The 9.0 Hz, 1 H, H-6), 7.31 (d, J6,8 = 2.0 Hz, 1 H, H-8), 8.01 (d, J5,6
=
=
=
2
product was collected by filtration and washed with cold 9.0 Hz, 1 H, H-5), 8.08 (d, J2′,3′ = J5′,6′ = 9.0 Hz, 2 H, H-2′ and
ethanol 96% (5 mL). The filtrate was concentrated and a H-6′), 9.21 (s, 1 H, 3-OH), 10.04 (s, 1 H, 4′-OH); δC (90.6 MHz,
second precipitation with ethanol 96% (5.4 mL) and water d6-DMSO) 56.2 (HCuC–CH2), 78.5 (HCuC), 79.0 (HCuC),
(1 mL) afforded a product that was collected by filtration and 101.5 (C-8), 114.6 (C-6), 115.5 (C-3′ and C-5′), 115.7 (C-10),
washed with cold ethanol 96% (5 mL). The two crops afforded 122.1 (C-1′), 126.2 (C-5), 129.3 (C-2′ and C-6′), 137.5 (C-3), 145.6
5b–5′b as crystals (1.21 g, 71%); νmax (neat)/cm−1 1604 (νCvO), (C-2), 156.0 (C-9), 159.0 (C-4′), 161.2 (C-7), 172.0 (C-4); HRMS
1661 (νCvO), 3276 (νuC–H); δH (360 MHz, d6-DMSO), 5b: 3.66 (t, (ESI): calculated for [C18H12O5
+
H]+: 309.0757. Found:
JHCuC,HCuC–CH = 2.5 Hz, 1 H, HCuC), 3.88 (s, 3 H, 3-OCH3), 309.0750. Calculated for: [C18H12O5 + Na]+: 331.0577. Found:
2
4.92 (d, JHCuC,HCuC–CH = 2.5 Hz, 2 H, HCuC–CH2), 6.57 (d, 331.0566.
2
J3′,5′ = 2.5 Hz, 1 H, H-3′), 6.61 (dd, J3′,5′ = 2.5 Hz, J5′,6′ = 9.0 Hz,
1 H, H-5′), 6.84 (d, J5,6 = 8.0 Hz, 1 H, H-5), 7.31 (dd, J2,6
4′-Hydroxy-3′-methoxy-7-propargyloxyflavonol 6b. 5 M NaOH
(5.5 mL, 27.5 mmol) was added to compounds 5b–5′b
=
2.0 Hz, J5,6 = 8.0 Hz, 1 H, H-6), 7.55 (d, J2,6 = 2.0 Hz, 1 H, H-2), (500 mg, 1.54 mmol). Then, H2O2 30% (790 μL, 7.73 mmol)
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was slowly added and the reaction mixture was stirred at r.t. vonoid), the source of Cu(I) (CuSO4·5H2O 0.05 eq. and sodium
for 1.25 hours, the mixture was then cooled in an ice bath and ascorbate 0.1 eq.; CuI 0.05 eq.) and flavonoid were added and
HCl 37% (2.3 mL) mixed with crushed ice (5 mL) was slowly the mixture was stirred at 60 °C overnight. The reaction
added. After precipitation, the mixture was filtered and mixture was then dissolved in water, acidified with 1 M HCl
washed with water (20 mL). The crude product was vigorously (pH ∼ 3.5) and kept in the fridge for one day. The solution was
stirred with a solution of 1 M NaHCO3 (10 mL). The mixture filtered through a PVDF membrane (0.45 μm) and the precipi-
was centrifuged (5000 rpm, 15 min) and the supernatant tate was washed with water and dried in a desiccator.
removed. The solid was again vigorously stirred with a solution
Triazole-linked C-glycosyl flavonoid 1a. From 6a (50.0 mg,
of 1 M NaHCO3 (8 mL) and then centrifuged (5000 rpm, 0.162 mmol), 8 (53.3 mg, 0.178 mmol), NaN3 (12.1 mg,
15 min). The supernatant was removed and the precipitate was 0.186 mmol) and CuSO4·5H2O (2 mg, 8 μmol) and Asc·Na
suspended in water (20 mL) and filtered and dried in a desic- (3.2 mg, 16.2 μmol) as a solid (84 mg, 91%) or CuI (1.5 mg,
cator to give 6b as a solid (335 mg, 64%); νmax (neat)/cm−1 8 μmol) (81 mg, 88%); νmax (neat)/cm−1 1604 (νCvO), 1730
1601 (νCvO), 3289 (νuC–H), 3490 (νH-bonded OH); δH (360 MHz, (νCvO), 3260 (νOH), 3485 (νH-bonded OH); δH (400 MHz, d6-
d6-DMSO) 3.70 (t, JHCuC,HCuC–CH = 2.5 Hz, 1 H, HCuC), 3.86 DMSO) 2.63 (dd, J1″,1′′′a = 9.0 Hz, J1′′′a,1′′′b = 15.5 Hz, 1 H, H-1′′′
2
(s, 3 H, 3′-OCH3), 4.99 (d, JHCuC,HCuC–CH = 2.5 Hz, 2 H, a), 2.89 (dd, J1″,1′′′b = 3.5 Hz, J1′′′a,1′′′b = 15.5 Hz, 1 H, H-1′′′b),
2
HCuC–CH2), 6.95 (d, J5′,6′ = 8.5 Hz, 1 H, H-5′), 7.08 (dd, J6,8
2.5 Hz, J5,6 = 9.0 Hz, 1 H, H-6), 7.35 (d, J6,8 = 2.5 Hz, 1 H, H-8), (m, 1 H, H-6″a), 3.54 (td, J1″,1′′′b = 3.5 Hz, J1″,2″ = J1″,1′′′a = 9.0 Hz,
7.73 (dd, J2′,6′ = 2.0 Hz, J5′,6′ = 8.5 Hz, 1 H, H-6′), 7.80 (d, J2′,6′ 1 H, H-1″), 3.68 (m, 1 H, H-6″b), 4.46 (t, J6″a,6″-OH = J6″b,6″-OH
=
2.95 (m, 1 H, H-2″), 3.03–3.21 (m, 3 H, H-3″, H-4″, H-5″), 3.42
=
=
2.0 Hz, 1 H, H-2′), 8.00 (d, J5,6 = 9.0 Hz, 1 H, H-5), 9.30 (s, 1 H, 5.0 Hz, 1 H, 6″-OH), 4.90 (d, J4″,4″-OH = 4.5 Hz, 1 H, 4″-OH), 4.95
3-OH), 9.71 (s, 1 H, 4′-OH); δC (90.6 MHz, d6-DMSO) 55.9 (d, J3″,3″-OH = 3.5 Hz, 1 H, 3″-OH), 5.17 (d, J2″,2″-OH = 5.0 Hz, 1 H,
(3′-OCH3), 56.3 (HCuC–CH2), 78.5 (HCuC), 79.0 (HCuC), 2″-OH), 5.35 (s, 2 H, H-6′′′), 5.56 (s, 2 H, H-3′′′), 6.95 (d, J2′,3′
101.6 (C-8), 111.8 (C-2′), 114.6 (C-6), 115.6 (C-10), 115.7 (C-5′), J5′,6′ = 8.5 Hz, 2 H, H-3′ and H-5′), 7.09 (dd, J6,8 = 2.0 Hz, J5,6
121.5 (C-6′), 122.4 (C-1′), 126.2 (C-5), 137.6 (C3), 145.4 (C-2), 9.0 Hz, 1 H, H-6), 7.44 (d, J6,8 = 2.0 Hz, 1 H, H-8), 7.99 (d, J5,6
=
=
=
147.4 (C-3′), 148.6 (C-4′), 155.9 (C-9), 161.2 (C-7), 171.9 (C-4); 9.0 Hz, 1 H, H-5), 8.09 (d, J2′,3′ = J5′,6′ = 8.5 Hz, 2 H, H-2′ and
HRMS (ESI): calculated for [C19H14O6 + H]+: 339.0863. Found: H-6′), 8.14 (s, 1 H, H-4′′′), 9.17 (s, 1 H, 3-OH), 10.04 (s, 1 H, 4′-
339.0850. Calculated for: [C19H14O6 + Na]+: 361.0683. Found: OH); δC (100.6 MHz, d6-DMSO) 43.2 (C-1′′′), 58.6 (C-3′′′), 61.3
361.0670.
(C-6″), 61.8 (C-6′′′), 70.4 (C-4″), 73.8 (C-2″), 75.8 (C-1″), 77.9
3′-(β-D-Glucopyranosyl)-2′-propanone (7). Prepared as pre- (C-3″), 80.9 (C-5″), 101.2 (C-8), 114.8 (C-6), 115.4 (C-3′ and C-5′
viously described,10 the volumes of solvents were optimized: a and C-10), 122.1 (C-1′), 126.1 (C-5), 126.2 (C-4′′′), 129.3 (C-2′
solution of D-glucose (2.50 g, 13.87 mmol), 2,4-pentanedione and C-6′), 137.5 (C-3), 141.8 (C-5′′′), 145.5 (C-2), 156.2 (C-9),
(1.75 g, 17.52 mmol), and NaHCO3 (1.75 g, 20.83 mmol) in 158.9 (C-4′), 162.1 (C-7), 172.0 (C-4), 201.6 (C-2′′′); HRMS (ESI):
water (10 mL) was refluxed overnight, then cooled to r.t. and calculated for [C27H27N3O11 + H]+: 570.1718. Found: 570.1718.
treated with Dowex 50 X-8 200 H+ to reach pH 5 (15.30 g). The Calculated for [C27H27N3O11
+
Na]+: 592.1538. Found:
resin was filtered, rinsed with H2O (25 mL) and the aqueous 592.1545; [α]2D4 = −10.9 (c = 0.25, DMSO).
solution was washed with AcOEt (20 mL) and concentrated to
Triazole-linked C-glycosyl flavonoid 1b. From 6b (50.3 mg,
afford 7 (3.05 g, 100%). Data were in accordance with those 0.149 mmol), 8 (66.4 mg, 0.222 mmol), NaN3 (15.0 mg,
previously described.10
0.231 mmol) and CuSO4·5H2O (1.8 mg, 7.3 μmol)–NaAsc
1′-Bromo-3′-(β-D-glucopyranosyl)-2′-propanone (8). To a solu- (2.9 mg, 14 μmol) as a solid (80 mg, 90%) or from 6b (50.2 mg,
tion of 7 (2.00 g, 9.08 mmol) in ethanol (20.2 mL) was added 0.148 mmol), 8 (77.6 mg, 0.259 mmol), NaN3 (17.2 mg,
pyridinium tribromide polymer-bound (5.905 g, 11.81 mmol) 0.265 mmol) and CuI (1.4 mg, 7.4 μmol) (76 mg, 85%);
and the mixture was stirred on an orbital shaker at r.t. for 2 h. νmax (neat)/cm−1 1596 (νCvO), 1732 (νCvO), 3279 (νOH);
The resin was filtered and washed with ethanol (3 × 10 mL). δH (400 MHz, d6-DMSO) 2.63 (dd, J1″,1′′′a = 9.0 Hz, J1′′′a,1′′′b
=
Water (1 mL) was added to the filtrate and the mixture was 15.5 Hz, 1 H, H-1′′′a), 2.89 (dd, J1″,1′′′b = 3.5 Hz, J1′′′a,1′′′b = 15.5
stirred for 15 min. A solution of Na2CO3 (1.4 M) was slowly Hz, 1 H, H-1′′′b), 2.95 (m, 1 H, H-2″), 3.03–3.20 (m, 3 H, H-3″,
added until pH = 6 (3.9 mL). The mixture was concentrated H-4″, H-5″), 3.42 (m, 1 H, H-6″a), 3.53 (td, J1″,1′′′b = 3.5 Hz, J1″,2″
in vacuo and the residue was purified by flash chromatography = J1″,1′′′a = 9.0 Hz, 1 H, H-1″), 3.68 (m, 1 H, H-6″b), 3.87 (s, 3 H,
(silica = 116 g, AcOEt–MeOH 9.5 : 0.5 (800 mL) then 9 : 1 (1 L)) 3′-OCH3), 4.45 (t, J6″a,6″-OH = J6″b,6″-OH = 5.0 Hz, 1 H, 6″-OH),
affording compound 8 as a white solid (1.480 g, 4.95 mmol, 4.89 (d, J4″,4″-OH = 4.0 Hz, 1 H, 4″-OH), 4.94 (d, J3″,3″-OH = 3.0 Hz,
54%). Data were in accordance with those previously 1 H, 3″-OH), 5.16 (d, J2″,2″-OH = 5.0 Hz, 1 H, 2″-OH), 5.35 (s, 2 H,
described.35,36
H-6′′′), 5.56 (s, 2 H, H-3′′′), 6.96 (d, J5′,6′ = 8.5 Hz, 1 H, H-5′),
7.09 (dd, J6,8 = 2.0 Hz, J5,6 = 9.0 Hz, 1 H, H-6), 7.48 (d, J6,8 = 2.0
Hz, 1 H, H-8), 7.75 (dd, J2′,6′ = 2.0 Hz, J5′,6′ = 8.5 Hz, 1 H, H-6′),
7.81 (d, J2′,6′ = 2.0 Hz, 1 H, H-2′), 7.99 (d, J5,6 = 9.0 Hz, 1 H,
General procedure for triazole-linked C-glycosyl flavonoid
synthesis
1′-Bromo-3′-(β-D-glucopyranosyl)-2′-propanone (7) was dis- H-5), 8.14 (s, 1 H, H-4′′′), 9.20 (s, 1 H, 3-OH), 9.66 (s, 1 H,
solved in molten PEG2000 (2.0 g mmol−1 of flavonoid) at 60 °C. 4′-OH); δC 100.6 MHz, d6-DMSO) 43.2 (C-1′′′), 55.9 (3′-OCH3),
After dissolution, sodium azide, water (0.29 mL mmol−1 of fla- 58.6 (C-3′′′), 61.3 (C-6″), 61.8 (C-6′′′), 70.4 (C-4″), 73.8 (C-2″), 75.8
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(C-1″), 77.9 (C-3″), 80.9 (C-5″), 101.3 (C-8), 111.7 (C-2′), 114.7
(C-6), 115.4 (C-10), 115.6 (C-5′), 121.6 (C-6′), 122.4 (C-1′), 126.1
(C-5), 126.2 (C-4′′′), 137.6 (C-3), 141.8 (C-5′′′), 145.3 (C-2), 147.4
(C-3′), 148.5 (C-4′), 156.2 (C-9), 162.1 (C-7), 172.0 (C-4), 201.6
5 Z. Kondora, D. P. Fuentes, C. Vogel, T. Patonaya and
K. Kónya, Synlett, 2016, 888.
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K. B. Mishra, B. B. Mishra, N. Singh, R. K. Singh and
V. K. Tiwari, Glycoconjugate J., 2015, 32, 127.
7 (a) M. A. Kuzemko, S. D. van Arnum and H. J. Niemczyk,
Org. Process Res. Dev., 2007, 11, 470; (b) M. Meldal and
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(C-2′′′); HRMS (ESI): calculated for [C28H29N3O12
+
H]+:
600.1824. Found: 600.1822. Calculated for [C28H29N3O12
+
Na]+: 622.1643. Found: 622.1626; [α]2D5 = −12.4 (c = 0.25,
DMSO).
Conclusions
We have described the total synthesis of a new class of pro-
ducts without the use of protective groups with overall yield of
41 (1a) and 33% (1b) from 2′,4′-dihydroxyacetophenone. These
syntheses were performed mainly using alternative solvents
such as water or PEG, or bio-based solvents, either for the syn-
thesis steps, workup or purification and the least toxic
reagents were preferred. Each step was optimized to decrease
the mass intensity related to the three operations of the
process (reaction, workup and purification). We proposed for
the first time such an analysis and a method to calculate these
metrics for a linear or convergent synthesis from the values
obtained for the individual steps. The analysis revealed that
for the synthesis of 1a and 1b the biggest part of the material
used was dedicated to the workups and purifications, this was
particularly dramatic when chromatography was necessary.
The nature of the auxiliary substances used for these oper-
ations should thus be considered as recently highlighted by
Jessop.37
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and the Université Paris-Sud for financial support.
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