Intramolecular dehydro-diels-alder reaction affords selective entry to arylnaphthalene or aryldihydronaphthalene lignans

Article abstract of DOI:10.1021/ol501853y

Intramolecular dehydro-Diels-Alder (DDA) reactions are performed affording arylnaphthalene or aryldihydronaphthalene lactones selectively as determined by choice of reaction solvent. This constitutes the first report of an entirely selective formation of arylnaphthalene lactones utilizing DDA reactions of styrene-ynes. The synthetic utility of the DDA reaction is demonstrated by the synthesis of taiwanin C, retrohelioxanthin, justicidin B, isojusticidin B, and their dihydronaphthalene derivatives. Computational methods for chemical shift assignment are presented that allow for regioisomeric lignans to be distinguished.

Full text of DOI:10.1021/ol501853y

Letter
pubs.acs.org/OrgLett
Open Access on 07/25/2015
Intramolecular Dehydro-Diels−Alder Reaction Affords Selective Entry
to Arylnaphthalene or Aryldihydronaphthalene Lignans
Laura S. Kocsis and Kay M. Brummond*
Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States
S
* Supporting Information
ABSTRACT: Intramolecular dehydro-Diels−Alder (DDA)
reactions are performed affording arylnaphthalene or aryl-
dihydronaphthalene lactones selectively as determined by
choice of reaction solvent. This constitutes the first report of
an entirely selective formation of arylnaphthalene lactones utilizing DDA reactions of styrene-ynes. The synthetic utility of the
DDA reaction is demonstrated by the synthesis of taiwanin C, retrohelioxanthin, justicidin B, isojusticidin B, and their
dihydronaphthalene derivatives. Computational methods for chemical shift assignment are presented that allow for regioisomeric
lignans to be distinguished.
rylnaphthalene lignans and their dihydro- and tetrahydro-
naphthalene derivatives are medicinally relevant com-
A
pounds with a wide range of pharmacalogical activity. Diphyllin
and justicidin B are both cytotoxic compounds and
demonstrate anticancer,1 antiparasitic,2 and antiviral3 activities
(Figure 1). β-Apopicropodophyllin displays pronounced
activity against the fifth-instar larvae of Brontispa longissima,
revealing the potential of podophyllotoxins as insecticides,4 in
addition to their possible application as immunosuppressive
agents.5 The most studied compound of this class is etoposide,
an approved anticancer drug that functions as a topoisomerase
inhibitor;6 however, several toxic side effects of etoposide have
resulted in a continued search for a better drug.7 A glycosylated
derivative diphyllin D11 has recently been shown to selectively
inhibit topoisomerase IIα despite its structural simplicity
compared to etoposide,8 highlighting the need for diphyllin
analogs. Herein we report the synthesis of eight arylnaph-
thalene and aryldihydronaphthalene lignan natural products via
a dehydro-Diels−Alder reaction of styrene-ynes.
Synthetic strategies used to prepare arylnaphthalene lignans
include intermolecular Diels−Alder reactions, such as reactions
of isobenzofurans 9 with dialkylacetylene dicarboxylates to
generate naphthyl diesters 10 (Scheme 1).9 Selective hydrolysis
of the C-3 ester of 10, followed by reduction of the resulting
carboxylic acid and subsequent acid-assisted lactonization yields
the lignan derivatives 11.9a,10 Alternatively, 10 can be accessed
by acid-catalyzed cyclizations11 or condensation reactions.10
Another common strategy for arylnaphthalene lignan synthesis
is by transition-metal-catalyzed multicomponent cycloaddition
reactions. Both dienes 13 and diynes 14 can be reacted with
Pd2(dba)3 and benzyne intermediates 12, leading to formation
of arylnaphthalenes 11.12,13
Figure 1. Representative structures of important arylnaphthalene
lignans and their derivatives (top) along with those synthesized using
the DDA reaction (bottom).
Based on previously reported results from our laboratory, we
envisioned that a thermal intramolecular dehydro-Diels−Alder
(DDA) reaction could be utilized to obtain both arylnaph-
thalene and aryldihydronaphthalene lignans from a single
precursor in only one synthetic step.14 To test the feasibility of
this strategy, the styrenyl precursor 15 was subjected to
microwave irradiation (MWI) at 180 °C for 20 min in 1,2-
dichlorobenzene-d4 (o-DCB-d4). This reaction afforded a 2:1
Received: June 26, 2014
Published: July 25, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
from 0.06 to 0.24 M did result in decreased selectivity for 16
(entry 4). Despite the observed selectivity for 16 and 17 in
PhNO2 and DMF, respectively, conducting the reaction in
NMP, a solvent of similar dielectric constant, resulted in a 1:12
mixture of 16:17 (entry 5).20
Scheme 1. Previous Synthetic Strategies To Access
Arylnaphthalene Lignans
The complete selectivity for arylnaphthalene products in the
presence of PhNO2 as the reaction solvent can be explained by
the oxidative ability of PhNO2. It has previously been shown
that PhNO2 can act as an oxidant to form heteroaromatic
systems when utilized as the reaction solvent.22 We reasoned
that if PhNO2 is acting as an oxidant, it need not be the primary
solvent and that the quantity present in the reaction could be
lessened. To test this hypothesis, incremental reductions were
made to the amount of PhNO2 added to a solution of 15 in o-
DCB, and the effect on the product selectivity of the
dehydrogenative DDA reaction was noted. Reducing the
amount of PhNO2 from 20% (v/v %) in o-DCB, which
showed complete selectivity for the naphthalene product 16 in
75% yield, to 10% resulted in a 13:1 ratio of 16:17. Decreasing
the concentration of PhNO2 further to 5% generated a 7:1 ratio
of 16:17, an almost proportional decrease in selectivity. These
results indicate that a 1:5 ratio of PhNO2 to o-DCB is the
minimal amount of PhNO2 required to achieve complete
selectivity for the naphthalene product in the dehydrogenative
DDA reaction.
mixture of lactones 16 and 17, consistent with previous DDA
reactions of precursors containing heteroatoms, esters, or
amides in the styrene-yne tether (Table 1, entry 1).15 The
Table 1. Controlling Selectivity of the DDA Reaction20
a
entry
solvent (ε)
concn (M)
yield (%)
16:17
With conditions in hand to prepare either the naphthalene or
dihydronaphthalene product selectively from a common
precursor, we set out to explore this reaction in the synthesis
of more functionalized substrates. The highly oxygenated
structures of many arylnaphthalene lignans and their derivatives
inspired us to prepare styrenyl precursors 21a−c containing
3,4-methylenedioxy and 3,4-dimethoxy functionalities (Scheme
2). Esterification of commercially available cinnamic acids 18a,b
using sulfuric acid and methanol followed by reduction with
DIBALH generated cinnamyl alcohols 19a,b in 76% to
quantitative yield over two steps. The cinammyl alcohols
were then coupled with arylpropiolic acids 20a,b via a DCC
coupling reaction to produce styrenyl precursors 21a−c in
66%−85% yield. Alternate coupling reagents to DCC were also
successfully utilized.23
Styrenyl precursors 21a−c were then subjected to the
optimized DDA reaction conditions. Irradiation of 21a in
PhNO2 for 5 min at 180 °C afforded a quantitative yield of
arylnaphthalene lactone 22 as a 2:1 mixture with its regioisomer
23 (Scheme 2). Likewise, irradiation of 21b under the same
reaction conditions resulted in an 83% yield of the arylnaph-
thalene lignan taiwanin C (1) as a 2:1 mixture with
retrohelioxanthin (5), which was then separated by HPLC for
characterization. Irradiation of 21c also provided a similar 2.3:1
ratio of arylnaphthalene lignans justicidin B (2) and
isojusticidin B (6) in 83% yield, which were readily separable
by column chromatography. Thus, four arylnaphthalene lignan
natural products were formed after a short reaction time and in
high combined yields. Attempts to increase the regioselectivity
of the DDA reaction by adding bulkier functionality to the
arylpropiolate, such as a 3,4-dimethoxy moiety, were not
successful. Similarly, irradiation of 21a for 5 min at 180 °C in
DMF led to formation of aryldihydronaphthalene 24 as a 2:1
mixture with its regioisomer 25 in 90% combined yield, while
irradiation of 21b produced 7,8-dihydrotaiwanin C (3) in 90%
yield as a 1.8:1 mixture with 7,8-dihydroretrohelioxanthin (7).
Irradiation of 21c gave collinusin (4) and 7,8-dihydroiso-
justicidin B (8) in 81% yield as a 1.5:1 ratio of products.24
1
2
3
4
5
o-DCB-d4 (9.93)
DMF (36.7)
0.06
0.06
0.06
0.24
0.06
75
90
93
−
2:1
0:1
PhNO2 (34.8)
PhNO2 (34.8)
NMP (32.2)
1:0
2.5:1
1:12
−
a
1
Ratios of 16:17 determined by H NMR spectroscopy.
potential of this DDA strategy was first recognized by Klemm16
and others who have validated this approach;17,18 however, low
yields, mixtures of naphthalene and dihydronaphthalene
products, and mixtures of regioisomers were often ob-
tained.16,19
With an eye toward increasing the synthetic utility of the
DDA reaction of styrene-ynes, we set out to control the
product selectivity by making variations to the reaction
conditions. While increasing the concentration of the reaction
mixture and altering the reaction temperature had minor to
moderate effects on product selectivity, modifying the solvent
from o-DCB to the more polar DMF resulted in exclusive
formation of 17 in 90% isolated yield after irradiation for 15
min at 180 °C (Table 1, entry 2). Changing the reaction
temperature and concentration in DMF did not affect the
product selectivity. DMF has previously been shown to act as a
hydrogen atom donor,21 and we speculated that this may be a
factor accounting for the selectivity observed when the DDA
reaction was performed in DMF. However, a similar substrate
was subjected to the DDA reaction conditions in DMF-d7 and
no deuterium incorporation was detected in the resulting
dihydronaphthalene product. Efforts to understand the
selectivity obtained for the DDA reaction in DMF are currently
underway.
Nitrobenzene (PhNO2) was also tested as a reaction solvent
because of its similar dielectric constant to DMF. Surprisingly,
irradiation of 15 for 15 min at 180 °C in PhNO2 produced 16
exclusively in 93% yield (Table 1, entry 3). While increasing the
temperature of the reaction did not affect the selectivity or yield
of the reaction in PhNO2, increasing the reaction concentration
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Letter
Scheme 2. Synthesis of Styrenyl Precursors and Their DDA
Reactions To Produce Lignan Natural Products
Figure 2. Average Δδ per carbon in taiwanin C (1) for EDF2 and
B3LYP functionals.
depicts the error associated for each carbon in taiwanin C (1),
where carbon 1 denotes the most downfield resonance. Also,
the maximum Δδ of calculated and experimental values were
significantly lower and the coefficient of determination (R2)
values higher for the EDF2 method. Reports by Bifulco27 and
Rychnovsky25a,c indicated that R2 values greater than 0.995 and
an average Δδ of less than 2 ppm, respectively, represent a
good match between predicted and experimental spectra, which
is consistent with our EDF2 results. In examples where multiple
conformers exist, as for the justicidin B analogs, a 13C NMR
spectrum was also predicted for a Boltzmann distribution of the
conformers. In most cases, the lowest energy conformer had
average Δδ and R2 values fitting the above criteria; however,
Boltzmann distribution predicted spectra typically showed
lower average Δδ and greater R2 values indicative of a better
match with experimental spectra (Table S27). Computational
predictions for 1H NMR spectra were also conducted for
taiwanin C deriviatives, and while the average Δδ were similar
for both the EDF2 and B3LYP functionals, they were not as
precise as those for the predicted 13C NMR spectra (Table
S28).28
In conclusion, solvent was shown to have a determinate
effect on product selectivity in the intramolecular DDA reaction
of styrene-ynes. Employing DMF as the reaction solvent
allowed for exclusive formation of aryldihydronaphthalene
lactones, while PhNO2 afforded arylnaphthalene lactones
selectively. This constitutes the first report of an entirely
selective formation of arylnaphthalene lactones utilizing a DDA
reaction of styrene-ynes. The synthetic potential of these
selective DDA reactions was realized by the preparation of eight
natural products from two precursors. The DDA approach to
arylnaphthalene and aryldihydronaphthalene lignans is cur-
rently being investigated for the preparation of novel
topoisomerase inhibitors, and the mechanism will be reported
shortly. Computational EDF2 methods were also applied for
the prediction of lignan 13C NMR spectra and demonstrated
good correlation with experimental spectra, often showing a
less than 1 ppm deviation. While the lignans synthesized herein
were previously characterized and are distinguishable, these
results validate the original structural assignments and the use
of computational calculations to aid in the differentiation of
lignan derivatives that have not been fully characterized.
Confirming the identity of lignan regioisomers and assigning
the individual resonances using NMR spectroscopy was
challenging, as these spectra were closely related. Similar
structural assignment challenges for natural and synthetic
products have been addressed by utilizing modern computa-
tional methods,25 where predicted NMR spectra are compared
with experiment. In light of these studies, computational
predictions of NMR spectra using Spartan 10 software were
conducted for the eight lignans to confirm the identity of each
regioisomer.26 Lowest energy conformers were first deter-
1
mined, and H and 13C NMR spectra were predicted with
either EDF2/6-31G* and/or B3LYP/6-31G* methods. Ex-
perimental and calculated 13C NMR spectra were matched
directly by descending order of chemical shift, similar to the
protocol employed by Goodman for when structural assign-
ments are lacking.25b
Comparison of the EDF2 and B3LYP functionals for the
taiwanin C derivatives showed that the EDF2 functional had an
average chemical shift deviation (Δδ) 2−6 times lower than
that of the B3LYP functional for 13C NMR data, indicating that
a more accurate prediction was obtained using the EDF2
method (Table S27). As a graphical representation of the
disparity between the EDF2 and B3LYP methods, Figure 2
ASSOCIATED CONTENT
* Supporting Information
Reaction optimization, experimental procedures, character-
ization of compounds, computational methods, and spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
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Organic Letters
Letter
(18) For a DDA reaction of diynes to directly access arylnaphthalene
lactones, see: Stevenson, R.; Weber, J. V. J. Nat. Prod. 1989, 52, 367.
(19) (a) Stevenson, R.; Block, E. J. Org. Chem. 1971, 36, 3453.
(b) Kashima, T.; Tanoguchi, M.; Arimoto, M.; Yamaguchi, H. Chem.
Pharm. Bull. 1991, 39, 192.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kbrummon@pitt.edu.
Notes
(20) For a comprehensive list of reaction conditions tested, see Table
S1 in the Supporting Information.
The authors declare no competing financial interest.
(21) Wassmundt, F. W.; Kiesman, W. F. J. Org. Chem. 1995, 60,
1713.
(22) (a) Yadagiri, B.; Lown, J. W. Synth. Commun. 1990, 20, 955.
(b) Charris, J.; Camacho, J.; Ferrer, R.; Lobo, G.; Barazarte, A.;
Gamboa, N.; Rodrigues, J.; Lopez, S. J. Chem. Res. 2006, 12, 769.
́
(23) EDC and BOP-Cl were tested and produced 21c in equivalent
yields and in higher purity.
(24) A recent report by Seo and Shin demonstrated that MWI of 21b
in Ac2O at 140 °C led to the regioselective production of 3 (ref 17d).
In our hands, irradiation of 21b utilizing the conditions reported by
Seo and Shin resulted in a 1.6:1 mixture of 3:7, a similar ratio to what
was obtained by irradiation in DMF.
(25) For lead references, see: (a) Rychnovsky, S. D. Org. Lett. 2006,
8, 2895. (b) Smith, S. G.; Goodman, J. M. J. Am. Chem. Soc. 2010, 132,
12946. (c) Willoughby, P. H.; Jansma, M. J.; Hoye, T. R. Nat. Protoc.
2014, 9, 643.
ACKNOWLEDGMENTS
■
The National Institute of Health (NIGMS P50GM067082),
University of Pittsburgh, and Andrew Mellon Predoctoral
Fellowship are gratefully acknowledged for financial support.
We would also like to thank Professor Dean Tantillo (UC
Davis) for his advice regarding computational calculations.
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