Advances in the methodology of a multicomponent synthesis of arylnaphthalene lactones

Article abstract of DOI:10.1039/b913685a

Material and energy inefficiencies in total synthesis can arise from a lack of step economy. Multicomponent syntheses have the potential to optimize step economy and, in turn, to minimize not only waste, but also exposure to hazardous chemicals. Therefore, multicomponent syntheses are of immense interest to the field of Green Chemistry. Herein is described a multicomponent synthesis of arylnaphthalene lignan lactones, which are valuable natural products with promising anticancer and antiviral properties. In an effort to improve our previously reported one-pot, multicomponent synthesis an approach using phenylacetylene, phenylpropargyl chloride, carbon dioxide, catalytic silver iodide, and catalytic 18-crown-6 ether was developed. This methodology was then successfully applied to the preparation of dehydrodimethylconidendrin and its regioisomer, dehydrodimethylretroconidendrin.

Full text of DOI:10.1039/b913685a

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PAPER
www.rsc.org/greenchem | Green Chemistry
Advances in the methodology of a multicomponent synthesis of
arylnaphthalene lactones†
Patrick Foley, Nicolas Eghbali and Paul T. Anastas*
Received 9th July 2009, Accepted 19th February 2010
First published as an Advance Article on the web 29th March 2010
DOI: 10.1039/b913685a
Material and energy inefficiencies in total synthesis can arise from a lack of step economy.
Multicomponent syntheses have the potential to optimize step economy and, in turn, to minimize
not only waste, but also exposure to hazardous chemicals. Therefore, multicomponent syntheses
are of immense interest to the field of Green Chemistry. Herein is described a multicomponent
synthesis of arylnaphthalene lignan lactones, which are valuable natural products with promising
anticancer and antiviral properties. In an effort to improve our previously reported one-pot,
multicomponent synthesis an approach using phenylacetylene, phenylpropargyl chloride, carbon
dioxide, catalytic silver iodide, and catalytic 18-crown-6 ether was developed. This methodology
was then successfully applied to the preparation of dehydrodimethylconidendrin and its
regioisomer, dehydrodimethylretroconidendrin.
In this earlier work, hydrolysis of the propiolate ester was
Introduction
required to access the acid starting material, which was then
converted to an acyl chloride. Reaction with a phenylpropargyl
alcohol to generate the diyne ester was then undertaken before
undergoing the thermal [2+2+2] cycloaddition in a separate step
to generate the desired arylnaphthalene lactone. In total, this
approach required four steps and used ethanol, dichloromethane
(DCM) and xylenes as solvents. Our group recently attempted
to resolve some of these shortcomings by developing a catalytic,
multicomponent/cycloaddition reaction which incorporates the
use of carbon dioxide as renewable feedstock. As hoped, this
synthesis proved more efficient than the traditional multi-step
syntheses in accessing the desired arylnaphthalene lactones.11
The achievements in the total synthesis of natural products
are among the most important contributions of the field of
organic chemistry. These achievements, however, have been a
source of very high waste production as a result of material
and energy inefficiencies and a lack of step–and atom–economy.
It is estimated that ~80% of waste generated during a typical
chemical transformation is due to use of solvent.1 Therefore,
in addition to the accumulation of losses due to incomplete
conversion, sometimes referred to as the “arithmetic demon,”
multi-step syntheses have an inherent waste associated with
solvent use at each step.2 One way to minimize this inherent
inefficiency is to perform as many transformations as is feasible
in a single reaction vessel.
In an effort to illustrate how one such approach can begin
to overcome some of the aforementioned limitations, the total
synthesis of arylnaphthalene lactones was undertaken (Fig. 1).
This class of compounds is an important class of pharmaceutical
interest due to its antiviral and antitumor activities.3-5 For
this reason an efficient synthesis to access a broad range of
arylnaphthalene lactones is highly desirable. Several synthetic
methodologies have been developed in recent years to access
both the arylnaphthalene core and more specific targets. Nev-
ertheless, most rely on multi-step syntheses that are deficient in
terms of Green Chemistry.6-9
Fig. 1 Representative naturally occurring arylnaphthalene lactone
lignans.
Notably, there was a previous synthesis in 1991 by one
of this paper’s co-authors (PTA) that utilized the same core
transformations and therefore serves as a useful comparison.10
In an effort to complete this work, the preparation of known
natural products and their closely related analogs was inves-
tigated; however the conditions reported earlier did not yield
the desired products. The 3,4-methylenedioxyphenylpropargyl
bromide reactant used for the original coupling appeared to be
consumed by side reactions before any product could be gener-
ated. This outcome is believed to be related to the instability of
electron-rich bromo-alkyne under the reaction conditions. With
the intention of improving the previous synthesis for application
to known natural products, we considered the use of alkyne
Center for Green Chemistry and Green Engineering at Yale, Yale
Chemistry Department, 225 prospect Street, New Haven, CT, 06511.
E-mail: Paul.Anastas@yale.edu; Fax: 1-203-436-8574;
Tel: 1-203-432-5215
† Electronic supplementary information (ESI) available: Details of the
green chemistry metrics calculation. See DOI: 10.1039/b913685a
888 | Green Chem., 2010, 12, 888–892
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Table 1 Leaving group and PTC screen
reagents bearing less reactive or more stable leaving groups such
as acetate, tosylate, and chloride. Further, a full investigation of
reaction parameters such as base, solvent, and phase transfer
catalyst (PTC) selection was undertaken.
Product
Entrya Reagent
1
Additive
—
Time
6
3
4
—
—
Results and discussion
In seeking new conditions to be applied to the synthesis of
natural products and their closely related analogs, we first
sought to modify the original arylnaphthalene lactone synthesis
(Scheme 1). Replacing the bromide leaving group with an
acetate group was first investigated but with no success, likely
owing to the insufficient electrophilicity of the acetate group.
Employment of a tosylate group was also attempted but required
a stoichiometric amount of halogenated salt to be used. It was
believed that in the presence of bromide salt, the tosylate could
perhaps be displaced producing in situ phenylpropargyl bromide.
2
3
4
5
6
7
8
KBr
6
6
6
6
6
6
6
—
—
TBP-Br
—
—
—
—
—
TBA-I
10% TBP-Br
60% TBP-Br
—
—
—
Trace
22
Trace
10
10
6
Scheme 1 General multicomponent approach to arylnaphthalene
lactones.
9
KBr
6
9
7
Following a similar line of thinking, a catalytic amount of
salt should be sufficient to drive the reaction since the halogen is
not part of the final product. However, a catalytic amount of salt
yielded only a small amount of product with a yield usually equal
to or less than the amount of salt originally added. Both of these
findings underscore once more the importance of the silver–
halide interaction as a driving force for the desired coupling.
Because the presence of a halogen group was apparently a
necessity for the success of the first coupling step, we turned our
attention to a chloride leaving group. Entries 8 to 16 in Table 1
present the results of this study. As expected, replacing the
substrate phenylpropargyl bromide by phenylpropargyl chloride
slowed the reaction rate and more than 20 h were needed to reach
completion. Interestingly the use of a phase transfer catalyst
such as tetrabutylammonium bromide or chloride significantly
increased the reaction rate. This was usually accompanied by
an increase of the carbonate byproduct, implying that the
potassium carbonate base could be solubilized by the presence
of the phase transfer catalyst. Following this observation, other
phase transfer catalysts such as 18-crown-6 were tested.
10
11
12
13
14
15
16
TBA-Br
TBA-Cl
TBA-I
6
23
28
26
24
28
30
34
15
22
17
16
19
20
22
6
6
TBP-Br
TBH-Br
18-Crown-6
6
6
6
The use of 18-crown-6 ether was the most effective and
resulted in a decrease of the carbonate byproduct. In addition
to being soluble in N,N-dimethylacetamide (DMA), 18-crown-
6 ether is known to trap monovalent cations. As such, it is
possible that the propiolic acid intermediate may exist in an ionic
state, coordinated with the crown ether/cation complex.12,13
Such a complex would likely increase the nucleophilicity of the
intermediate and thus decrease byproduct formation.
18-Crown-6
3 A mol sieve
18
a All reactions were performed on a 0.5 mmol scale at 100 ◦C under 1
atm of CO2 using 0.2 eq. of PTC or salt where indicated. All yields are
isolated after chromatography. TBP = tetrabutylphosphonium, TBA =
tetrabutylammonium, TBH = tributylhexadecylphosphonium.
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Table 2 Solvent and base screen
Product
Entry
Base
Solvent
3
4
1
2
K2CO3
K2CO3
BMIM-Br
Propylene
carbonate
Propylene
carbonate
NMP
DMA
DMA
DMA
DMA
Trace
19.3
Trace
9.7
3
K3PO4
Trace
Trace
4
5
6
7
8
K2CO3
t-BuOK
K3PO4
Hunig’s base
DBU
—
—
40.7
4.0
—
20.3
2.0
—
Fig. 2 Dehydrodimethylconidendrin 1 and dehydrodimethylretro-
conidendrin 2.
—
—
All reactions were performed on a 0.5 mmol scale at 100 ◦C under 1 atm
of CO2 using 0.2 eq. of 18-crown-6 for 6 h. All yields were determined
by 1H NMR.
Table 3 Performance metrics for the two syntheses
General and green
chemistry metrics
Original synthesis10,19
33.2
Improved synthesis
46.2
In an effort to further improve the reaction conditions, we
monitored the effect of various bases and polar solvents on the
yield of the reaction. Results are presented in Table 2.
%yield
(for both regioisomers)
No. of steps
Solvents used
E-factor
Atom economy (%)
3
2
DCM, xylenes
139.1
73.5
DMA
35.0
73.5
Since ammonium salts proved to be quite effective in acceler-
ating the rate of the reaction, it was envisioned that ammonium-
based ionic liquids, which are polar solvents, could potentially
be used as both solvent and catalyst.14 DMA was therefore
replaced by butylmethylimidazolium bromide (BMIM-Br) and
butylmethylimidazolium chloride (BMIM-Cl), however only
traces of the desired products could be observed by 1H NMR. It
is very likely that the silver catalyst may have been consumed by
side reactions involving the formation of a carbene.15 Further,
switching from DMA to propylene carbonate in an effort to
increase the solubility of carbon dioxide significantly favored
the formation of the carbonate byproduct.
Alternative bases were investigated in the hopes of minimizing
byproduct formation and accelerating the reaction rate. Inter-
estingly, the use of an amine base such as Hunig’s base yielded
no desired product formation, nor did it appear to displace
chloride. Potassium phosphate generated the desired product,
but at a rate much slower than that of potassium carbonate, with
starting materials still present after 18 h. Of the alternative bases
investigated, potassium t-butoxide worked the best with yields
similar to those observed when using potassium carbonate.
However, owing to the more corrosive nature of this base, it was
not deemed an improvement for this synthesis. Ultimately, and
in accordance with Inoue’s original work, potassium carbonate
seems to remain the best base to be used in this system.16
The best conditions obtained for the unsubstituted arylnaph-
thalene lactone synthesis were then applied to the synthesis
of a tetramethoxy-substituted arylnaphthalene lactone natural
product analog (Scheme 2). The chloride precursor 5 was
obtained from the 3,4-dimethoxyphenylpropargyl alcohol in
84% yield.
43% yield. Isolation of the individual isomers, however, required
chromatography.
Some green chemistry metrics were calculated for both the
original approach and this new approach and are presented in
Table 3.17,18 Both regioisomers were considered as the desired
product. The original synthesis was examined with the propio-
late intermediate as starting point. It is important to note that the
improved synthesis has the added advantage of generating this
propiolic acid intermediate in situ, an advantage not reflected
in the metrics and which eliminates an otherwise additional
synthetic step.
Scheme 2 Optimized route to dehydrodimethylconidendrin 1 and
dehydrodimethylretroconidendrin 2.
These metrics compare the halogen activation, coupling,
and cyclization steps used to access the desired conidendrin
molecules. These steps were chosen to highlight how both
syntheses share the same atom economy while requiring dramat-
ically different resource inputs. Although the E-factor is still not
ideal for this improved two-step synthesis, it constitutes a con-
siderable improvement as compared to the original approach. As
is commonly the case, solvent accounted for the vast majority
of the waste generated by both routes.
These new conditions were found to offer two of the four
possible regioisomers in 55% yield, nearly an identical yield to
that of the unsubstituted system. Only trace amounts of the
minor regioisomers were observed, which is consistent with
previous findings reported by Stevenson and coworkers.4 The
two major isomers, shown in Fig. 2, were formed in a 2 :
1 ratio and could be isolated as a clean mixture by simple
trituration of the crude extract with ethyl acetate and hexane in
890 | Green Chem., 2010, 12, 888–892
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could be purified by column chromatography using a 30 →
35 → 40% gradient of EtOAc–hexane to yield 63 mg (33%) of
1 and 42 mg (22%) of 2, in addition to several mixed fractions.
Dehydrodimethylconidendrin (1): 1H NMR (500 MHz, CDCl3)
d 8.30 (1 H, d, J 57.0), 7.19 (1 H, d, J 0.8), 7.05 (1 H, s), 6.98
(1 H, s), 6.91–6.87 (1 H, m), 6.83 (1 H, s), 5.17 (2 H, dd, J 14.9,
14.9), 3.99 (3 H, s), 3.93 (3 H, s), 3.82 (3 H, s), 3.76 (3 H, s).
13C NMR (126 MHz, CDCl3) 171.64, 151.96, 150.10, 149.29,
148.94, 137.91, 132.15, 131.63, 129.90, 128.61, 124.07, 121.55,
121.39, 112.16, 111.64, 107.64, 104.11, 69.56, 56.05, 56.03, 55.94,
55.86; m/z (HRMS) 381.13307 (M + H+. C22H21O6 requires
Experimental section
Representative procedure for the silver-catalyzed one-pot
synthesis of arylnaphthalene lactones 3 and 4
To a round bottom flask fitted with a condenser and a stirrer bar
was introduced the catalyst AgI (23.4 mg, 0.05 mmol) under CO2
atmosphere (1 atm). After addition of 1 mL of DMA, potassium
bicarbonate (160.1 mg, 0.5 mmol), phenylacetylene (51 mg,
0.5 mmol), 3-chloro-2-phenyl-1-propyne (75 mg, 0.5 mmol), and
phase transfer catalyst (0.1 mmol) the mixture was placed in an
oil bath at 100 ◦C. After 6 h, the reaction mixture was cooled and
extracted with ethyl acetate to afford a 2.5 : 1 mixture of products
3 and 4. The products were purified by column chromatography
using 1 : 5 ethyl acetate–hexane. 4-Phenylnaphtho[2,3-c]furan-
1(3H)-one (3): 1H NMR (500 MHz, CDCl3) d 5.20 (s, 2H), 7.32
(d, 2H, J 7.55 Hz), 7.49 (m, 5H), 7.74 (d, 1H, J 7.55 Hz), 8.03
(d, 1H, J 6.45 Hz), 8.46 (s, 1H); 13C NMR (125 MHz, CDCl3) d
69.5, 123.0, 125.9, 126.4,126.7, 128.4, 129.0, 129.3, 130.1, 133.7,
134.1, 134.9, 135.8, 138.4, 171.2; m/z (HRMS) 261.09063 (M +
H+. C18H12O2 requires 261.0910). 9-Phenylnaphtho[2,3-c]furan-
1(3H)-one (4): 1H NMR (500 MHz, CDCl3) d 5.39 (s, 2H), 7.32
(m, 2H), 7.42 (t, 1H, J 7.85, 8.35 Hz), 7.47 (m, 3H), 7.58 (t, 1H, J
7.45 Hz), 7.74 (d, 1H, J 8.80 Hz), 7.84 (s, 1H), 7.90 (d, 1H, J 8.35
Hz); 13C NMR (125 MHz, CDCl3) d 68.1, 120.2, 126.7, 128.0,
128.1, 128.3, 128.6; m/z (HRMS) 261.0907 (M + H+. C18H12O2
requires 261.0910).
1
381.133265). Dehydrodimethylretroconidendrin (2): H NMR
(500 MHz, CDCl3) d 7.64 (1 H, s), 7.13 (1 H, s), 7.07 (1 H, s),
6.98 (1 H, d, J 8.2), 6.91 (1 H, d, J 8.1), 6.86 (1 H, s), 5.33 (2 H,
s), 3.99 (3 H, s), 3.92 (3 H, s), 3.82 (4 H, d, J 11.4), 3.72 (3 H, s).
13C NMR (126 MHz, CDCl3) d 170.44, 152.20, 150.43, 149.28,
148.90, 140.39, 140.03, 133.59, 129.25, 127.56, 122.98, 118.74,
118.55, 113.81, 111.18, 106.40, 68.42, 60.81, 56.49, 56.38, 56.23,
56.21; m/z (HRMS) 381.13300 (M + H+. C22H21O6 requires
381.133265). NMR data for these compounds are consistent
with those previously reported.20
Conclusions
The silver-catalyzed multicomponent synthesis of arylnaphtha-
lene lactones was successfully applied to the preparation of
compounds of the conidendrin class of lignans. This approach
enables facile access to the arylnaphthalene lactone core using
a multicomponent approach involving two aryl alkynes, carbon
dioxide, and a silver catalyst. Unlike the previously reported
multicomponent approach, these new conditions appear to
be robust in their tolerance for electron-donating groups on
the electrophilic component of the tandem coupling reaction,
thus enabling access to the naturally occurring compounds of
arylnaphthalene lactones and their analogs. In summary, this
greener route is more energy and material efficient, generates
less waste, and does not rely on chlorinated solvent.
Despite these advances, this approach still has several limi-
tations in terms of green chemistry. Ideally, hazardous reagents
such as thionyl chloride and 18-crown-6 would be replaced by
more benign reagents. Further, although the yields were high
enough to provide a viable and abbreviated route to this class
of molecules, higher conversions are desirable. Future work
will focus on product selectivity and will involve continued
application of this methodology to explore the full scope of
this approach to accessing various naturally occurring lignans.
Preparation of 3,4-dimethoxyphenylpropargyl chloride (5)
In a round bottom flask under 1 atm N2, DMA (8.0 ml) and
3,4-dimethoxypenylpropargyl alcohol (490 mg, 2.55 mmol) were
cooled to 0 ◦C in an ice bath while stirring. The thionyl chloride
(0.2 ml, 2.8 mmol) was then added dropwise and the solution
was allowed to slowly warm to rt over several hours. Once the
reaction was complete as indicated by TLC, the mixture was
quenched with H2O, neutralized with NaHCO3, extracted 3¥
with EtOAc, dried with Na2SO4, filtered and concentrated. The
crude mixture was purified by column chromatography using 1
: 12 EtOAc–hexane to afford 450 mg (84%) of a yellow oil that
1
crystallized upon cooling (5): H NMR (400 MHz, CDCl3) d
7.09 (1 H, dd, J 1.8, 8.3), 6.98 (1 H, d, J 1.8), 6.83 (1 H, d, J 8.3),
4.41 (2 H, s), 3.91 (3 H, s), 3.90 (3 H, s). 13C NMR (126 MHz,
CDCl3) d 150.35, 149.00, 125.72, 114.86, 114.51, 111.33, 86.94,
82.77, 56.31, 56.29, 31.82; m/z (HRMS) 211.05187 (M + H+.
C11H12ClO2 requires 211.052034).
Dehydrodimethylconidendrin and dehydrodimethylretro-
conidendrin (1 and 2)
Acknowledgements
In a round bottom tube under 1 atm of CO2, compound 5
(105 mg, 0.5 mmol), 3,4-dimethoxyphenylacetylene (81 mg,
0.5 mmol), AgI (12 mg, 0.05 mmol), K2CO3 (70 mg, 0.5 mmol),
This research was supported by Yale University. The authors are
grateful to Dr TuKiet T. Lam for mass spectroscopy analysis.
˚
18-crown-6 (27 mg, 0.1 mmol), DMA (1.4 ml) and 3 A mol
Notes and references
sieves (~100 mg) were combined. The solution was then heated at
100 ◦C for 15 h. The mixture was then cooled, diluted with H2O,
neutralized with 1 N HCl, extracted 3¥ with EtOAc, washed
with brine, dried with Na2SO4, filtered, and concentrated. 78 mg
(41%) of a 2 : 1 mixture of compounds 1 and 2 could then
be isolated through trituration with EtOAc, or the material
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