Silver-catalyzed one-pot synthesis of arylnaphthalene lactone natural products

Article abstract of DOI:10.1021/np900667h

Naturally occurring arylnaphthalene lactone lignans have demonstrated a variety of valuable medicinal chemistry properties and have therefore been of continued interest to drug discovery research. Our group has demonstrated a silver-catalyzed one-pot synthesis of the arylnaphthalene lactone core using carbon dioxide, phenylpropargyl chloride, and phenylacetylene. This new approach has been employed in the synthesis of six arylnaphthalene lactone natural products: retrochinensin (1), justicidin B (2), retrojusticidin B (3), chinensin (4), justicidin E (5), and taiwanin C (6). Additionally, an arylnaphthalene lactone regioisomer was isolated (9), which we refer to as isoretrojusticidin B.

Full text of DOI:10.1021/np900667h

J. Nat. Prod. 2010, 73, 811–813
811
Silver-Catalyzed One-Pot Synthesis of Arylnaphthalene Lactone Natural Products
Patrick Foley, Nicolas Eghbali, and Paul T. Anastas*
Center for Green Chemistry and Green Engineering at Yale UniVersity, 225 Prospect Street, New HaVen, Connecticut 06511
ReceiVed October 20, 2009
Naturally occurring arylnaphthalene lactone lignans have demonstrated a variety of valuable medicinal chemistry properties
and have therefore been of continued interest to drug discovery research. Our group has demonstrated a silver-catalyzed
one-pot synthesis of the arylnaphthalene lactone core using carbon dioxide, phenylpropargyl chloride, and phenylacetylene.
This new approach has been employed in the synthesis of six arylnaphthalene lactone natural products: retrochinensin
(1), justicidin B (2), retrojusticidin B (3), chinensin (4), justicidin E (5), and taiwanin C (6). Additionally, an
arylnaphthalene lactone regioisomer was isolated (9), which we refer to as isoretrojusticidin B.
Arylnaphthalene lactones are a subgroup of the lignan class of
molecules that are characterized by a phenylpropanoid dimer motif.
Many of these arylnaphthalene lignans are components of traditional
herbal remedies and have received increasing attention over the
past several decades owing to their cytotoxic,1 antiviral,2 fungicidal,
antiprotozoal,3 and antiplatelet4,5 activities in cell-based assays. New
natural products within this class of compounds continue to be
reported,6,7 and ongoing studies have led to a better understanding
of their biosynthetic origins with the hopes of finding a viable
biotechnological production methodology.8-11 Additionally, the
desire to access these molecules for further investigation has led
to the development of many successful synthetic approaches for
arylnaphthalene lignans, some dating back to as early as 1895.12-18
In an effort to explore new synthetic options for accessing this class
of molecules, our group has recently demonstrated a silver-
catalyzed, multicomponent approach to access the arylnaphthalene
lactone core.19,20 Here this multicomponent methodology was
applied to the synthesis of the naturally occurring arylnaphthalene
lignans retrochinensin (1), justicidin B (2), retrojusticidin B (3),
chinensin (4), justicidin E (5), and taiwanin C (6).
Results and Discussion
Similar to the approach first explored by Klemm et al.,21,22 our
approach utilizes an intramolecular cycloaddition reaction of a 1,6-
diyne ester to generate the arylnaphthalene core. The advantage of
the present work, however, is that it further incorporates a
methodology developed by Inoue et al.23 that allows for the diyne
ester to be generated in situ from readily prepared acetylene
precursors using catalytic silver iodide, potassium carbonate, and
carbon dioxide at 1 atm. These conditions allow for the formation
of a phenylpropargylic acid intermediate from phenylacetylene that
can then participate in a nucleophilic attack on a phenylpropargyl
halide, thus generating the diyne ester. Performing this reaction in
a suitable solvent, such as N,N-dimethylacetamide (DMA), at
elevated temperature (100 °C) further allows for intramolecular
cyclization to take place, thus generating the desired aryl naphtha-
lene lactone.
In efforts to optimize this methodology using model systems it
was observed that the selection of chloride as the leaving group
(LG) of the phenylpropargyl halide component offered higher
conversion than when performed with phenylpropargyl bromide,
likely due to the greater stability of the chloride under the reaction
conditions. A variety of other LGs were investigated as well,
including tosylate, triflate, and acetate; however, all of these gave
low yields or no product all. These results suggested that the driving
force of the silver halide interaction is critical to the success of the
reaction.
In addition to substrate selection, the use of a phase transfer
catalyst (PTC) was required to promote desirable conversion rates.
Potassium carbonate and silver halides are largely insoluble in DMA
and thus require the presence of a PTC to participate effectively
under these conditions. Although several ammonium- and phos-
phonium-based PTC reagents were found to be reasonably effective,
18-crown-6 ether appeared to give the best results in this capacity.
Using the most favorable conditions observed in our model
systems, it was envisioned that we could access a variety of
naturally occurring arylnaphthalene lactones beginning with known
starting materials. Treating 3,4-methylenedioxyphenylpropargyl
alcohol and 3,4-dimethoxyphenylpropargyl alcohol with thionyl
chloride in DMA generated the desired phenylpropargyl chlorides
7a and 7b in 96% and 84% yields, respectively. These substituted
phenylpropargyl chlorides, together with phenylacetylenes 8a and
8b, could then be taken on to the multicomponent tandem coupling
reaction in the permutations described in entries 1-3 in Scheme
1.
The overall yield from entry 2 in Scheme 1 was comparable to
what was observed in the model systems, whereas the yields from
* To whom correspondence should be addressed. Tel: 1-203-432-5215.
Fax: 1-203-436-8574. E-mail: Paul.Anastas@yale.edu.
10.1021/np900667h  2010 American Chemical Society and American Society of Pharmacognosy
Published on Web 05/07/2010

812 Journal of Natural Products, 2010, Vol. 73, No. 5
Foley et al.
Scheme 1. Preparation of Arylnaphthalene Lactones 1-6 and Respective Isolated Yieldsa
a Reagents and conditions: (a) SOCl2, DMA; (b) K2CO3, 18-crown-6, 4 Å molecular sieves, DMA, 100 °C.
entries 1 and 3 were slightly lower than expected. These results
can likely be attributed to instability of phenylacetylene 8a under
the reaction conditions. Indeed we found that this compound
required storage at 0 °C away from light to prevent degradation.
Regardless, we were able to obtain significant quantities of all of
the desired natural products with this fairly abbreviated synthetic
route.
Although two predominant regioisomers were formed in each
of these reactions, it is mechanistically feasible to expect a small
percentage of regioisomers with substitution on the 7 and 8 positions
of the naphthalene core. There was, in fact, evidence in entries 1
and 3 of the presence of these regioisomers by 1H NMR, but they
were present in only trace quantities and isolation was not deemed
practical based on the scale at which we were working. However,
with regard to entry 2, it was possible to isolate regioisomer 9 (as
shown), which we provisionally refer to as isoretrojusticidin B. To
our knowledge this compound has been reported only once
previously as a semisynthetic derivative of a natural extract.24 This
would then constitute the first fully synthetic preparation of this
compound.
thalene lactones and closely related analogues, both naturally
occurring and otherwise, in a parallel or high-throughput fashion,
thereby allowing for rapid exploration of the properties of this class
of compounds.
Experimental Section
General Experimental Procedures. NMR spectra were recorded
1
on Bruker Avance 400 and 500 MHz spectrometers as specified. H
and 13C NMR spectra were measured and reported in ppm (δ) by using
the CDCl3 residual solvent peaks (δ H 7.27 and δ C 77.2, respectively)
as internal standards. ESMS and FT-ICR were performed on a Q-TOF
Micro (Waters Corporation, Milford, MA) instrument and a 9.4T Fourier
transform ion cyclotron resonance MS instrument (Bruker Daltonics,
Billerica, MA), respectively. Chromatographic separations were carried
out by conventional column chromatography on Siliflash F60 silica
gel (230-450 mesh).
3,4-Methylenedioxyphenylpropargyl Chloride (7a). DMA (40 mL)
and 3,4-methylenedioxyphenylpropargyl alcohol (1.7 g, 9.6 mmol) were
combined in a round-bottom flask under N2 and cooled in an ice bath
while stirring. Thionyl chloride (1.1 mL, 14.5 mmol) was then added
dropwise. The solution was allowed to stir for 3 h while warming to
rt. Once the reaction was complete as indicated by TLC, the mixture
was quenched with H2O, neutralized with NaHCO3, extracted three
times with EtOAc, dried with Na2SO4, filtered, and concentrated. The
crude mixture was purified by column chromatography using 1:12
1
EtOAc/hexane to afford 1.8 g (96%) of 7a as a white solid: H NMR
(500 MHz, CDCl3) δ 7.01 (dd, J ) 1.4, 8.0, 1H), 6.91 (d, J ) 1.2,
1H), 6.78 (d, J ) 8.0, 1H), 6.00 (s, 2H), 4.38 (s, 2H); 13C NMR (126
MHz, CDCl3) δ 148.8, 147.8, 127.1, 115.6, 112.2, 108.9, 101.8, 86.7,
82.62, 31.7.
3,4-Dimethoxyphenylpropargyl Chloride (7b). In a round-bottom
flask under N2, DMA (8.0 mL) and 3,4-dimethoxyphenylpropargyl
alcohol (490 mg, 2.55 mmol) were cooled in an ice bath while stirring.
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 three times
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 7b as a yellow oil that crystallized
Chromatographic separation was problematic using an isocratic
solvent system and thus required a continuous gradient from 10%
to 40% ethyl acetate in heptanes to achieve separation. Where mixed
fractions were encountered, the desired product could often be
obtained through simple trituration using heptane with a minimal
amount of ethyl acetate, followed by filtration.
Despite the slightly attenuated yields of the multicomponent step,
this reaction can generate fully elaborated arylnaphthalene lactones
from readily accessible, if not commercially available, phenylacety-
lene precursors in a single, catalytic step. This suggests that this
methodology could be used to generate a broad range of arylnaph-
1
upon cooling: H NMR (400 MHz, CDCl3) δ 7.09 (dd, J ) 1.8, 8.3,
1H), 6.98 (d, J ) 1.8, 1H), 6.83 (d, J ) 8.3, 1H), 4.41 (s, 2H), 3.91 (s,
3H), 3.90 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 150.3, 149.0, 125.7,
114.9, 114.5, 111.3, 86.9, 82.8, 56.3, 56.3, 31.8; HRMS m/z 211.05187
[M + H]+ (calcd for C11H12ClO2, 211.05203).

Arylnaphthalene Lactone Natural Products
Journal of Natural Products, 2010, Vol. 73, No. 5 813
Representative Procedure for the Arylnaphthalene Lactone
Multicomponent Tandem Coupling Reaction to give Retrochinensin
(1) and Justicidin B (2). In a round-bottom tube equipped with an
airtight septum, phenylpropargyl chloride 7b (105 mg, 0.5 mmol),
phenylacetylene 8a (73 mg, 0.5 mmol), silver iodide (12 mg, 0.05
mmol), 18-crown-6 (27 mg, 0.1 mmol), DMA (2.0 mL), and 4 Å
molecular sieves (100 mg) were combined. The flask was then purged
of atmosphere under vacuum and subsequently placed under 1 atm of
CO2 using a balloon-needle apparatus. The reaction mixture was then
stirred at 100 °C for 15 h under CO2 atmosphere. The reaction was
cooled to rt, diluted with EtOAc, neutralized with 1 N HCl, extracted
three times with EtOAc, washed once with brine, dried with Na2SO4,
filtered, and concentrated. The crude residue was then purified with
flash column chromatography using a 10% f 20% f 30% f 40%
EtOAc/heptane gradient. Trace contaminants coeluted with compound
1 and thus required trituration with heptane and a drop of EtOAc. A
white solid (1, 28 mg, 16%) was isolated after filtration. Compound 2
(28 mg, 16%, of white solid) was collected from concentrated desired
fractions without further purification.
5 was isolated as a white solid (32 mg, 18%) and compound 6 was
isolated as an off-white solid (25 mg, 14%).
Justicidin E (5): 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.32
(s, 1H), 7.11 (s, 1H), 6.98 (d, J ) 8.3, 1H), 6.83-6.78 (m, 2H), 6.10
(m, 4H), 5.26-5.16 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 171.4,
150.5, 148.4, 148.2, 147.7, 138.4, 133.4, 132.6, 131.2, 129.6, 124.7,
122.7, 121.6, 109.6, 109.0, 105.2, 102.0, 101.8, 101.4, 69.4; HRMS
m/z 349.07078 [M + H]+ (calcd for C20H13O6, 349.070665). NMR
spectra were in excellent agreement with those reported previously.14
Taiwanin C (6): 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.23
(s, 1H), 7.14 (s, 1H), 6.99 (d, J ) 7.8, 1H), 6.84-6.80 (m, 2H),
6.13-6.08 (m, 4H), 5.40 (d, J ) 1.0, 2H); 13C NMR (126 MHz, CDCl3)
δ 170.2, 150.3, 149.1, 148.0, 147.9, 140.5, 140.2, 135.0, 130.9, 128.8,
123.9, 119.5, 119.3, 110.9, 108.6, 104.1, 104.1, 102.2, 101.7, 68.4;
HRMS m/z 349.07080 [M + H]+ (calcd for C20H13O6, 349.070665).
NMR spectra were in excellent agreement with those reported previ-
ously.14
Acknowledgment. This research was supported by Yale University.
The authors are grateful to Dr. T. T. Lam for mass spectroscopy
analysis.
1
Retrochinensin (1): H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H),
7.35 (s, 1H), 7.13 (s, 1H), 7.07 (d, J ) 8.2, 1H), 6.94 (dd, J ) 1.9, 8.1,
1H), 6.87 (d, J ) 1.9, 1H), 6.13 (s, 2H), 5.28-5.18 (m, 2H), 4.01 (s,
3H), 3.92 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 171.9, 150.9, 149.8,
149.5, 148.8, 138.8, 133.8, 133.3, 131.7, 128.9, 125.0, 122.1, 122.0,
112.6, 112.1, 105.7, 102.5, 102.2, 69.9, 56.5, 56.4; HRMS m/z
365.10185 [M + H]+ (calcd for C21H17O6, 365.101965). NMR spectra
were in excellent agreement with those reported previously.15
Justicidin B (2): 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.20
(s, 1H), 7.12 (s, 1H), 6.99 (d, J ) 7.6, 1H), 6.88 (s, 1H), 6.85 (d, J )
9.5, 1H), 6.12 (d, J ) 1.5, 1H), 6.07 (d, J ) 1.5, 1H), 5.40 (s, 2H),
4.07 (s, 3H), 3.83 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 170.4, 152.2,
150.5, 148.0, 147.9, 140.1, 139.9, 133.6, 129.3, 128.8, 123.9, 118.9,
118.7, 111.0, 108.6, 106.4, 106.2, 101.7, 68.5, 56.5, 56.2; HRMS m/z
365.10200 [M + H]+ (calcd for C21H17O6, 365.101965). NMR spectra
were in excellent agreement with those reported previously.15
Retrojusticidin B (3), Chinensin (4), and Isoretrojusticidin B (9).
Phenylpropargyl chloride 7a (97 mg, 0.5 mmol) and phenylacetylene
8b (81 mg, 0.5 mmol) were reacted according to the general procedure.
Combination and concentration of desired fractions after chromatog-
raphy gave compounds 3 (56 mg, 31%), 4 (46 mg, 26%), and 9 (8.0
mg, 0.6%) without further purification.
1
Supporting Information Available: H and 13C NMR spectra of
compounds 1-6, 7a,b, and 9 are available free of charge via the Internet
at http://pubs.acs.org.
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Retrojusticidin B (3): 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H),
7.33 (s, 1H), 7.12 (s, 1H), 7.02 (d, J ) 8.2, 1H), 6.89 - 6.86 (m, 2H),
6.14 (d, J ) 1.3, 1H), 6.11 (d, J ) 1.3, 1H), 5.25 (s, 2H), 4.08 (s, 3H),
3.89 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 172.0, 152.4, 150.6, 148.7,
148.1, 138.4, 132.3, 132.1, 130.3, 130.2, 124.6, 123.1, 121.8, 109.9,
109.4, 108.1, 104.4, 101.9, 69.9, 56.5, 56.3; HRMS m/z 365.10193 [M
+ H]+ (calcd for C21H17O6, 365.101965). NMR spectra were in excellent
agreement with those reported previously.15
Chinensin (4): 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.24 (s,
1H), 7.15 (s, 1H), 7.06 (d, J ) 8.2, 1H), 6.94 (dd, J ) 2.0, 8.1, 1H),
6.89 (d, J ) 1.9, 1H), 6.11 (s, 2H), 5.41 (s, 2H), 4.01 (s, 3H), 3.90 (s,
3H); 13C NMR (126 MHz, CDCl3) δ 169.8, 149.9, 148.9, 148.6, 148.5,
140.4, 139.8, 134.6, 130.5, 127.2, 122.4, 118.9, 118.7, 113.3, 110.7,
103.7, 103.6, 101.8, 67.9, 55.9, 55.8; HRMS m/z 365.10217 [M + H]+
(calcd for C21H17O6, 365.101965). NMR spectra were in excellent
agreement with those reported previously.15
1
Isoretrojusticidin B (9): H NMR (500 MHz, CDCl3) δ 8.45 (s,
1H), 7.90 (d, J ) 9.1, 1H), 7.45 (d, J ) 9.1, 1H), 6.91 (d, J ) 7.8,
1H), 6.84 -6.77 (m, 2H), 6.06 (d, J ) 3.1, 2H), 5.15 (AB, J ) 15.2,
2H), 4.03 (s, 3H), 3.34 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 171.7,
152.9, 147.6, 147.1, 144.5, 141.4, 133.5, 131.3, 130.8, 130.8, 127.8,
127.4, 121.4, 121.3, 115.6, 109.6, 108.1, 101.5, 70.3, 61.1, 56.9; HRMS
m/z 365.10197 [M + H]+ (calcd for C21H17O6, 365.101965). NMR
spectra were in excellent agreement with those reported previously.24
Justicidin E (5) and Taiwanin C (6). Phenylpropargyl chloride 7a
(97 mg, 0.5 mmol) and phenylacetylene 8a (73 mg, 0.5 mmol) were
reacted according to the general procedure. Once the desired fractions
were combined and concentrated, both product 5 and 6 required
trituration with heptane and a drop of EtOAc. After filtration compound
NP900667H