Catalytic one-pot microwave assisted synthesis of 4-azapodophyllotoxin derivatives and rational design of experiment

Article abstract of DOI:10.1039/c5nj01785h

A catalytic one-pot microwave assisted synthesis of 4-azapodophyllotoxin has been described. Rational design of experiment has been used to obtain the reaction yield.

Full text of DOI:10.1039/c5nj01785h

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Catalytic one-pot microwave assisted synthesis of 4-
azapodophyllotoxin derivatives and rational design of experiment
Peng Chang,a,b Alexandre Aillerie,a,b Marion Kosmala,a,b,c Sylvain Pellegrini,a,b Till Bousquet,a,b
Muriel Biganb,c* and Lydie Pélinskia,b*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A catalytic one-pot microwave assisted synthesis of 4-
azapodophyllotoxin has been described. Rational design of
experiment has been used to perform reaction yield.
Podophyllotoxin (PT) 1, a lignin found in herbaceous genus of
Podophyllum, has been described to be a strong microtubule
destabilizing agent by interaction with the colchicine site of
tubulin.1 The basic structure of PT was modified in order to
obtain more potent and less toxic anticancer agents. This
Fig. 1 Podophyllotoxin and their derivatives
research has led to etoposide
2 and teniposide 3, two
glycoside derivatives, used in chemotherapy (Figure 1).2
However, these compounds present several limitations, such
as poor water solubility, development of drug resistance,
metabolic inactivation and toxic effects. To overcome such
problems, significant effort in the synthesis of 4-
azapodophyllotoxins such as 4, possessing anticancer activity
has been carried out by a number of researchers.3 Particularly,
multicomponent reactions starting from substituted anilines,
aldehydes and tetronic acid, constitute an ideal tool to access
a wide range of these 4-azapodophyllotoxin derivatives.4 This
method approach is particularly efficient when aniline is
substituted by electron-donating groups.
Following our interest on synthesis of 4-azapodophyllotoxins,5
we wish to report a catalytic one-pot synthesis of their
derivatives starting from 2-aminobenzyl alcohols combining
high speed microwave with design of experiment (DoE)
approach. In recent years, catalyzed reactions of 2-aminoaryl
Scheme 1 Catalytic addition of dimedone on 4-aminobenzyl alcohol
This experimental design was subjected to a second-order
multiple regression analysis to explain the behavior of the
system using the least square regression methodology.
This experimental design consisted of 25 trials including 24 full
factorial design points (Table 1, entries 1-16), 8 axial points
(Table 1, entries 17-24)9 and 2 central points (Table 1, entries
25 and 26).10
The low and high factor levels are coded Xi = -1 and Xi = +1
respectively. The relation between coded and natural variables
was given as follows: ꢀꢁ = ꢀꢁꢂ + ∆ꢀꢁꢃꢁ, with ui the real value,
ꢀꢁꢂ the real value at the center point, Xi the coded value and
+∆ꢀꢁ the step change value.
The central composite experimental design was represented
by a mathematical model obtained by multiple regressions and
fitted with a second order polynomial function represented by
the following equation where y is the predicted response:
alcohol with
β-ketoesters via benzylation/propargylation-
cyclisation to produce quinoline derivatives have been
developed as an alternative method of the Friedländer
annulation.6 Contrarily to this previous reaction, our method
presents
the
advantage
to
easily
access
to
didehydroquinolines,
derivatives.
particularly
4-azapodophyllotoxin
Our initial exploration started with the reaction of 4-
aminobenzyl alcohol 5a with dimedone to produce
compound 7a (Scheme 1).7 The reaction was performed in
toluene in the presence of catalytic amount of p-
ꢄ = ꢅꢂ + ꢆ ꢅꢇ ꢃꢇ + ꢆ ꢅꢇꢇ ꢃꢈ + ꢆ ꢅꢇꢉ ꢃꢇꢃ + ꢊ
ꢉ
ꢇ
6
ꢇ
ꢇ
ꢇꢉ
Coefficients of the model
according to the relation: ꢅ = (ꢃꢋꢃ)ꢌꢍꢃꢋ. ꢄ
X is the experiment matrix in coded variables;
β are determined by matrix algebra
a
toluenesulfonic acid (PTSA). For the synthesis of 7a, a study
was performed using a face centered composite design8 with
the aim to optimize four variables including reaction
temperature (X1), time (X2), amount of dimedone (X3), and
amount of catalyst (X4) (Table 1).
X t
is the
−1 is the reverse of the
( )
by X, is the matrix of the answers.
X t X
transposed experiment matrix and
X t
matrix product of
y
β0, βi, βii, βij are the regression coefficients for intercept,
linear, quadratic and interaction terms respectively.
ε
represents the experimental error. Real values of each
a.Université de Lille, 59000 Lille, France
variable as well as the response of each experiment are
described on Table 1 and results given were analyzed using the
software Modde 5.0 (Umetrics, Sweden).
b.Unité de Catalyse et de Chimie du Solide, UMR CNRS 8181, ENSCL, Université de
Lille 1, 59652 Villeneuve d’Ascq, France
c. Probiogem, Polytech’Lille, 59655 Villeneuve d’Ascq, France
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Table 1 Design of experiment for screening of the synthesis of 7a
Exp.a
Temp
(°C)
(X1)
100
140
100
140
100
140
100
140
100
140
100
140
100
140
100
140
80
T
(min)
(X2)
20
20
40
40
20
20
40
40
20
20
40
40
20
20
40
40
30
30
10
50
30
30
30
30
30
30
Dimedone
(equiv)
(X3)
1.5
Catalystb
(mol%)
(X4)
5
Yieldc
(%)
1
38
80
38
73
64
83
59
80
64
67
69
2
1.5
5
3
1.5
5
4
1.5
5
86,0
83,4
80,8
78,2
75,5
72,9
70,3
67,7
65,1
62,5
59,9
57,3
5
2
5
6
2
5
7
2
5
8
2
5
9
1.5
10
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
1.5
10
1.5
10
1.5
10
75
64
67
68
74
13
74
66
74
69
78
83
68
73
68
Fig
3. 3D surface contour plots in function of the amount catalyst and
temperature factor
2
10
2
10
2
10
2
10
1.75
1.75
1.75
1.75
1.25
2.25
1.75
1.75
1.75
1.75
7.5
7.5
7.5
7.5
7.5
7.5
2.5
12.5
7.5
7.5
160
120
120
120
120
120
120
120
120
84,6
82,8
81,0
79,1
77,3
75,5
73,6
71,8
69,9
68,1
66,3
64,4
a General conditions: 5a (50 mg, 0.25 mmol), dimedone (x equiv) in toluene (2 mL)
with y mol% of PTSA as catalyst under microwave irradiation. b p-Toluenesulfonic
acid. cNMR yield with 1,3,5-trimethoxybenzene as internal reference.
Fig 4. 3D surface contour plots in function of the amount catalyst and dimedone
Figure 2 summarizes the results of the effects of each factors
and possible interactions between them. The models were
found to be significant at 95% confidence level by the F-test
and the coefficients R2 of models are above 0.97 indicating
that over 97% of the data could be explained by the model.
The results revealed a strong and positive influence of the
factor X1 (temperature) on the yield. Furthermore, the
interactions between X1 and the X4 (amount of catalyst) and
between X3 (amount of dimedone) and X4 were found
significant. Only the factor X2 (time) had a negligible effect on
the yield indicating that it could be set at its lowest level of 20
minutes.
Figures 3 and 4 illustrate the 3D response surface plots of the
second order polynomial model for the studied response
(yield) and highlight the interactions X1X4 and X3X4. As
observed in Figure 3, the highest yield (85%) was predicted at
a high temperature (140 °C) with a small amount of catalyst for
a reaction time of 20 min and 2 equivalents of dimedone. In
Figure 4, with the reaction conditions set to 20 min at 140 °C, a
85% yield was predicted when a small amount of catalyst and a
high quantity of dimedone were combined.
In conclusion, the most favorable conditions to apply were
found to be a 20 min reaction time at 140 °C with an amount
of 2 equivalents of dimedone and in the presence of 2 mol% of
catalyst.
20
10
0
Under these optimized conditions, we explored the reaction
using different Brønsted and Lewis acids catalyzed formation
of didehydroquinolines (Table 2). As shown in Table 2, in the
absence of catalyst a low yield of 42% was obtained (entry 1).
Although all catalysts have furnished the product with yields
ranging from 67 to 95% (entries 2-7), ZnCl2 was proven to be
the most effective.
-10
-20
Fig 2 Effects of different factors and their interactions on the yield
2 | J. Name., 2012, 00, 1-3
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Table 2 Effect of different catalysts on the reaction of 5a with dimedone 6a
With the optimized conditions in hand, the scope of the
reaction was explored with various substituted
aminobenzylalcohols and nucleophiles (Table 3). In a typical
procedure, the reaction was performed with 2 equivalents of
ketone and 2 mol% of ZnCl2 at 140 °C for 20 min. Starting from
aminoalcohol 5a
cyclohexanone, ethyl 3-phenylacetoacetate, tetronic acid and
2-hydroxynaphthoquinone afforded the compounds 7b in
, the reaction with ketones such as
Entry
Catalyst
none
PTSA
H2SO4
TFAc
Yieldb (%)
-e
1
2
3
4
5
6
7
42
85
81
82
67
95
81
60-93% yields (entries 1-4). The reaction was then carried out
with tetronic acid and diversely substituted aminoalcohols
(entries 5-7). Excellent yields were obtained starting from
aminoalcohol 5b and 5c (entries 5 and 6). However, the
presence of methoxy electron-donating groups on both phenyl
groups led a lower 58% yield due to the aromatization of
compound 7h (entry 7). The same reaction with 5e with
dimedone instead of tetronic acid led to 7i in a better yield of
85% (entry 8).
PAd
ZnCl2
CuCl2
aReaction conditions: 5a (50 mg, 0.25 mmol), dimedone (2 equiv) in toluene (2
mL) with 2 mol% of catalyst under microwave irradiation for 20 min at 140°C.
bNMR yield. cTFA: Trifluoroacetic acid. dPA: Phenylphosphinic acid
Table 3. Using optimal condition for some reagentsa
Entry
1
Aminoalcohol
Ketone
Product
Yield (%)b
93
5a
5a
7b
7c
2
3
60
60
5a
7d
O
O
4
5
6
5a
5b
5c
7e
7f
68
98
93
N
H
7g
7
8
5d
5e
7h
7i
58
85
aReaction run employing 5 (0.25 mmol), ketone (2 equiv) in toluene (2 mL) with 2 mol% of ZnCl2 under microwave irradiation for 20 min at 140 °C. bIsolated yield.
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5
6
A. Aillerie, V. L. de Talancé, A. Moncomble, T. Bousquet and
L. Pélinski, Org. Lett., 2014, 16, 2982.
In summary, we described a catalytic one-pot microwave
assisted synthesis of 4-azapodophyllotoxin derivatives. The
statistical design of experiments approach has allowed the
screening for an optimal system for this synthesis. Further
studies on an enantioselective approach are currently
underway in our laboratory.
J. Fan, C. Wan, G. Sun and Z. Wang, J. Org. Chem., 2008, 73
8608.
,
7
8
M. Kidwai and S. Rastogi, Heteroatom Chem., 2005, 16, 138.
G. E. P. Box and K. B. Wilson, J. Roy. Statist. Soc. Ser. B, 1951,
13, 1.
9
Star distance α between the axial points and the center of
the domain is generally given by:
in this study).
α
= [nf]0.25 (nf is equal to 2k
Experimental
10 Central points are repeated and conducted to estimate the
experimental error.
Typical experimental procedure (optimized) for synthesis of
7a:7 a mixture of 4-aminobenzylalcohol 5 (50 mg, 0.25 mmol),
dimedone 6 (70 mg, 0.50 mmol) and 2 mol% ZnCl2 (0.9 mg) in
toluene (2 mL) were placed in a 10 mL microwave tube
equipped with a magnetic stirrer. The sealed tube was placed
in the cavity of the microwave reactor and irradiated for 20
min at 150 °C. After evaporation of solvent, the residue was
crystallized in a CH2Cl2/pentane mixture. M.p. 192-194°C; 1H
NMR (DMSO, 300 MHz)
δ 9.39 (s, 1H), 7.18 (m, 4H), 7.14-7.01
(m, 3H), 6.93 (dd, J = 7.9 and 1.0 Hz, 1H), 6.85 (td, J = 7.4 and
1.2 Hz, 1H), 5.06 (s, 1H), 2.51 (d, J = 16.6 Hz, 1H), 2.40 (d, J =
16.8 Hz, 1H), 2.17 (d, J = 16.0 Hz, 1H), 2.00 (d, J = 15.8 Hz, 1H),
1.03 (s, 3H), 0.95 (s, 3H). 13C NMR (DMSO, 75 MHz)
δ 192.7,
151.7, 148.7, 136.1, 129.5, 128.0, 126.8, 126.7, 125.7, 125.5,
122.7, 115.2, 106.2, 50.2, 39.7, 32.0, 29.1, 26.7.
Acknowledgements
The authors are thankful to the institutions that support our
laboratory (Centre National de la Recherche Scientifique,
Université de Lille). This research was supported by the
“Conseil Régional Nord-Pas de Calais” (program PRIM, grant
for AA).
Notes and references
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New Journal of Chemistry
A catalytic one-pot microwave assisted synthesis of 4-azapodophyllotoxin has been described. Rational design of experiment has been used to perform reaction yield.