Naphthalene analogues of lignans

Article abstract of DOI:10.1021/jo0263364

The methodology for the synthesis of podophyllotoxin and thuriferic acid-type lignans has been applied to derivatives carrying a naphthalene moiety. Starting from the 1,3-dithiane of 2-naphthaldehyde afforded the expected analogues in the 2,1-naphthalene series. The preferred conformations of these compounds are influenced by the bulky naphthalene system. By contrast, 1,8-bridged products were obtained from the 1,3-dithiane of 1-naphthaldehyde. In this series, polycyclic naphthalene lignan analogues were isolated after deprotection and/or desulfurization reactions. The cyclizations produced in this process are due to the proximity between the 3,4,5-trimethoxyphenyl moiety and the reacting C-2 of the 1,3-dithiane ring.

Full text of DOI:10.1021/jo0263364

Na p h th a len e An a logu es of Lign a n s†
Blanca Madrigal, Pilar Puebla, Rafael Pela´ez, Esther Caballero, and Manuel Medarde*
Laboratorio de Quı´mica Orga´nica y Farmace´utica, Facultad de Farmacia, Universidad de Salamanca,
Campus Miguel de Unamuno, E-37007 Salamanca, Spain
medarde@usal.es
Received August 19, 2002
The methodology for the synthesis of podophyllotoxin and thuriferic acid-type lignans has been
applied to derivatives carrying a naphthalene moiety. Starting from the 1,3-dithiane of 2-naph-
thaldehyde afforded the expected analogues in the 2,1-naphthalene series. The preferred conforma-
tions of these compounds are influenced by the bulky naphthalene system. By contrast, 1,8-bridged
products were obtained from the 1,3-dithiane of 1-naphthaldehyde. In this series, polycyclic
naphthalene lignan analogues were isolated after deprotection and/or desulfurization reactions.
The cyclizations produced in this process are due to the proximity between the 3,4,5-trimethox-
yphenyl moiety and the reacting C-2 of the 1,3-dithiane ring.
In tr od u ction
logical activities, the most interesting of which is its
anticancer potential as a DNA Topoisomerase II10 inhibi-
tor.
Lignans are a very interesting class of natural prod-
ucts1 due to their pharmacological properties,2 their great
number of structural possibilities,3 and the chemical
approaches4 to their synthesis. Among the lignan family,
the cytotoxic podophyllotoxin5 has been the most studied
and its derivative etoposide is currently used in cancer
chemotherapy.6 The synthesis of podophyllotoxin and
other arylnaphthalene lignans has been accomplished by
several methods, whose most demanding challenge is to
complete the stereochemical arrangement in the C ring:
the so-called cis-trans (7′-8′ cis; 8-8′ trans) stereo-
chemistry. During our previous work, we prepared and
assayed several families of heterolignans7 carrying het-
erocyclic moieties in their structure.8 Azatoxin9 is the
most representative heterolignan with well-known bio-
As part of our research on lignans, a new approach to
the synthesis of podophyllotoxin based on key epimer-
ization reactions, from the (7′,8′-8,8′)-trans-trans ster-
eochemistry of the major cyclization product to the
required (7′,8′-8,8′)-cis-trans stereochemistry of podo-
phyllotoxin (Scheme 1), has been described.11
With this procedure we have been able to synthesize
several new families of compounds carrying heterocyclic
ring systems instead of the A,B-ring system of podophyl-
lotoxins (Figure 1).12 Finally, the naphthyl and hetero-
cyclic (furan, thiophene, carbazole) analogues of thuriferic
acid and podophyllotoxin have been evaluated for their
cytotoxicity.13 On the basis of this research, the existence
of a different mechanism of action for thuriferic acid and
* To whom correspondence should be addressed.
† This paper is dedicated in memory of our colleague Dr. Benedicto
del Rey.
(1) (a) Rao, C. B. S. Chemistry of Lignans; Andhra University
Press: Waltair, 1978. (b) Ayres, D. C.; Loike, J . D. Lignans: Chemical,
Biological and Clinical Properties; Cambridge University Press: Cam-
bridge, 1990.
(2) (a) Gordaliza, M.; Castro M. A.; Miguel del Corral, J . M.; San
Feliciano, A. Curr. Pharm. Des. 2000, 6, 1811. (b) Damayanthi, Y.;
Lown, J . W. Curr. Med. Chem. 1998, 5, 205.
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Synthesis 1992, 719.
(5) J ardine, I. Podofilotoxins. In Anticancer Agents Based on Natural
Products Models; Cassady, J . M., Douras, J . D., Eds.; Academic Press:
New York, 1980; Chapter 9.
(6) (a) Hande, K. R. Eur. J . Can. 1998, 34, 1514. (b) Sta¨helin, H.;
von Wartburg, A. From Podophyllotoxin Glucoside to Etoposide. In
Progress in Drug Research; 1989; Vol. 33, pp 169-266.
(7) Ramos, A. C.; Pela´ez- Lamamie´ de Clairac, R.; Medarde, M.
Heterocycles 1999, 51, 1443.
(8) Medarde, M.; Pela´ez-Lamamie´ de Clairac, R.; Tome´, F.; Lo´pez,
J . L.; San Feliciano, A. Arch. Pharm. (Weinheim) 1995, 328, 403.
(9) Leteurtre, F.; Madalengoitia, J . S.; Orr, A.; Guzi, T. J .; Lehnert,
E. K.; Macdonald, T. L.; Pommier, Y. Cancer Res. 1992, 52, 4478.
(10) (a) Eymin, B.; Solary, E.; Chevillard, S.; Dubrez, L.; Goldwasser,
F.; Duchamp, O.; Genne, P.; Leteurtre, F.; Pommier, Y. Int. J . Cancer
1995, 63, 268. (b) Leteurtre, F.; Sackett, D. L.; Madalengoitia, J .;
Kohlhagen, G.; Macdonald, T.; Hamel, E.; Paull, K. D.; Pommier, Y.
Biochem. Pharmacol. 1995, 49, 1283.
(11) Medarde, M.; Ramos, A. C.; Caballero, E.; Lo´pez, J . L.; Pela´ez-
Lamamie´, R.; San Feliciano, A. Tetrahedron Lett. 1996, 37, 2663.
(12) Ramos, A.C.; Pela´ez, R.; Lo´pez, J . L.; Caballero, E.; Medarde,
M.; San Feliciano, A. Tetrahedron 2001, 57, 3963.
10.1021/jo0263364 CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/19/2002
854
J . Org. Chem. 2003, 68, 854-864

Naphthalene Analogues of Lignans
SCHEME 1. Syn th etic Ap p r oa ch to
P od op h yllotoxin
competition of other cyclization regiochemistries. The
higher reactivity at position 1 of the naphthalene system
must direct the cyclization step of the 2-naphthyl podor-
hizol-like intermediate to form the 2,1-fused naphthalene
analogue (Scheme 2A). According to our previous meth-
odology, the 2,1-naphtho analogue of podophyllotoxin
would be obtained in a stereocontrolled way from the
cyclized synthetic intermediate (Scheme 1). Thuriferic
acid analogues would be obtained through lactone open-
ing by treatment with base.
The electrophilic cyclization procedure is not suited for
the preparation of the 2,3-naphtho-podophyllotoxin re-
gioisomeric products. Taking into account that yatein is
a known intermediate in the biosynthetic pathway to
podophyllotoxin,14 the naphthyl analogue depicted in
Scheme 2B can be used in cell culture feeding experi-
ments to assay such a cyclization. Preliminary attempts15
in this direction have so far been unsuccessful, and future
work must be done to check the feasibility of this
approach.
For the synthesis of 1,2-naphtho-podophyllotoxin re-
gioisomers, a competition between cyclization at the re-
quired 2-position and cyclization at the 8-position could
be foreseen (Scheme 2C). Position 2 is less reactive, but
cyclization at the preferred 8-position would form a highly
strained seven-membered ring, with a planar 1,8a,8 moi-
ety and a trans-fused lactone. Under these circumstances,
1,2-naphthopodophyllotoxin analogues could be produced
in the cyclization.
its analogues with respect to the podophyllotoxin and its
analogues has been proposed due to the very dissimilar
structure-activity relationships observed for both fami-
lies of compounds.
With this plan, we decided to study the synthesis of
2,1-naphthalene (starting from 2-(2-naphthyl)-1,3-dithiane)
and 1,2-naphthalene (starting from 2-(1-naphthyl)-1,3-
dithiane) analogues of podophyllotoxins using the pro-
posed methodology.
Syn th esis fr om 2-(2-Na p h th yl)-1,3-d ith ia n e (1).
Starting from 2-(2-naphthyl)-1,3-dithiane (1), lithiation
at position 2 with butyllithium followed by conjugate
addition to 5H-furan-2-one and alkylation with 3,4,5-tri-
methoxybenzaldehyde, at low temperature in the pres-
ence of 2 equiv of TMEDA, yielded a 2:1 mixture of the
erythro (2) and threo (3) alcohols. Minor amounts of non-
alkylated lactone 4 were observed in some reactions
(Scheme 3).
These results are consistent with those usually ob-
served when 2-aryl-1,3-dithianes are used as starting
materials.16 The cyclization of isolated compounds or
mixtures of 2 and 3 under different acidic conditions17
always yielded the same cyclization products at the
1-position of the naphthalene. The stereochemical out-
come of the cyclization is the formation of compounds 5
F IGURE 1.
To prepare further derivatives for the activity assays
and to demonstrate the usefulness of our approach in the
synthesis of new lignan analogues, we decided to study
the preparation of naphtho analogues of podophyllotoxins
and thuriferic acid starting from 1- and 2-naphthalde-
hydes. Here, we report the results obtained during this
research.
(13) Madrigal, B.; Puebla, P.; Ramos, A.; Pela´ez, R.; Gra´valos, D.;
Caballero, E.; Medarde, M. Bioorg. Med. Chem. 2002, 10, 303.
(14) Lewis, N. G.; Davin, L. B. Lignans: Biosynthesis and Function.
In Comprehensive Natural Products Chemistry. Pinto, B. M., Ed.;
Pergamon Press: Oxford, 1999. Vol. 3, pp 639-712.
(15) Pras, N.; Koulhman, A. Farmaceutische Biology. Rijks Univer-
siteit, Groningen, The Netherlands. Personal communication, 2001.
(16) (a) Eich, E.; Pertz, H.; Schulz, J .; Fesen, M. R.; Mazumder, A.;
Pommier, Y. J . Med. Chem. 1996, 39, 86. (b) Medarde, M.; Pela´ez-
Lamamie´ de Clairac, R.; Tome´, F.; Lo´pez, J . L.; San Feliciano, A. Arch.
Pharm. (Weinheim) 1994, 327, 91. (c) Hanessian, S.; Murray, P. J . J .
Can. Chem. 1986, 64, 2231. (d) Michael, Y. L.; Paddon-Row, N.; Houk,
K. N. J . Am. Chem. Soc. 1988, 110, 3648. (e) Zimmerman, H. E.;
Traxler, M. D. J . Am. Chem. Soc. 1975, 79, 1920.
Meth od s a n d Resu lts
The synthesis of the three types of naphthalene
analogues of podophyllotoxin was planned as depicted in
Scheme 2.
2,1-Naphtho-podophyllotoxin could be synthesized start-
ing from the dithioketal of 2-naphthaldehyde, an ap-
proach that would lead to the final product without the
(17) (a) Ogiku, T.; Yoshida, S. I.; Ohmizu, H. E.; Iwasaki, T. J . Org.
Chem. 1995, 60, 4585. (b) Gonza´lez, A. G.; de la Rosa, R.; Trujillo, J .
M. Tetrahedron 1986, 42, 3899. (c) Pelter, A.; Ward, R. S.; Prichard,
M. C.; Kay, I. T. Tetrahedron Lett. 1985, 26, 6377.
J . Org. Chem, Vol. 68, No. 3, 2003 855

Madrigal et al.
SCHEME 2
SCHEME 3 a ,b
a
Each structure depicted represents the relative stereochemistry of a racemic mixture. Yields under structures: isolated compounds.
Yields under arrows: purified crude of reaction. bReagents and conditions: (a) 1.6 M BuLi, THF, -78 °C, 45 min, then 5H-furan-2-one,
THF, -78 °C, 3 h, then 3,4,5-trimethoxybenzaldehyde, THF, TMEDA, -50 °C, 12 h; (b) TFA, CH2Cl2, rt, 24 h; (c) THF/H2O, HgO, 0 °C,
then BF3‚OEt2, 24 h, rt.
(trans-trans, isopodophyllotoxin-type; major product)
and 6 (cis-trans, podophyllotoxin-type; minor product),
as usually described for such a cyclization reaction.18
Deprotection of 5 and 6 gave ketoderivatives 7 and 8,
with no change in the relative stereochemistry at posi-
tions 8 or 8′. The H-7′ NMR signal clearly differentiates
both stereoisomers, showing a large coupling constant
(trans) for the isopodophyllotoxin analogue 7 and a strong
deshielding for the podophyllotoxin analogue 8, which has
H-7′ near the plane containing A-B-C rings, deshielded
by the naphthalene.
Compound 7 is the key intermediate for the synthesis
of podophyllotoxin and thuriferic acid analogues19 (which
can also be obtained from 8). The opening of the lactone
(18) Brown, E.; Daugan, A. Tetrahedron 1989, 45, 141.
856 J . Org. Chem., Vol. 68, No. 3, 2003

Naphthalene Analogues of Lignans
SCHEME 4 a
a
Reagents and conditions: (a) KOH/MeOH (1%), 1.5 h, rt; (b) CH2N2/ether, 5 min; (c) p-TsOH, benzene, ∆, 7 h; (d) HCl, CH2Cl2, 2 h,
rt.
TABLE 1. Com p a r ison of 1H NMR Da ta of Th u r ifer a tes a n d Th eir Na p h th o An a logu es
H-7′
H-8′
H-8
methyl thuriferate
4.64 d 3.7
4.33 d 11.7
5.41 s
5.38 d 1.8
5.46 s
3.91 d 3.7
3.58 dd 11.7; 10.8
4.04 s
3.75 dd 1.8; 4.7
3.91 d 4.2
methyl 9-chlorodihydrothuriferate
3.26 ddd 10.8; 3.1; 2.9
11
12
14
3.18 ddd 8.3; 5.4; 4.7
3.17 ddd 10.4; 5.4; 4.2
ring by treatment with base yields a mixture of the
expected acidic derivative 9 and the product from metha-
nol conjugate addition 10 (Scheme 4). Both compounds
were converted into methyl esters 11 and 12 with
diazomethane, which also yielded 13 as a byproduct.
Conjugate addition products of type 12 are easily ob-
tained from unsaturated ketones, as it was confirmed by
the isolation of 14 after treatment of 11 with hydrochloric
acid. The methoxy derivative 12 was converted into a
thuriferic acid analogue 11 by acidic treatment.
The relative stereochemistry at H-7′-H-8′ for thuriferic
acid and derivatives was unequivocally established as
trans in the literature, on the basis of coupling constants,
NOE studies, and theoretical calculations,20 but the data
for the naphtho analogues are different from those
described. As shown in Table 1, there are significant
variations in the chemical shifts and coupling constants.
These differences can be explained by the effect of the
naphthalene ring oriented toward the 3,4,5-trimethox-
yphenyl residue, thus triggering a change in the confor-
mational preference for the substituents on C-7′ and C-8′
in the naphtho analogues. The most striking variation
lies in the small coupling constants between H-7′-H-8′-
H-8 for the 9-chloro (14) and 9-methoxy (12) derivatives,
in agreement with a trans-trans equatorial arrangement
for these hydrogens, whereas in the 9-chloro (9-methoxy)
derivatives from methyl thuriferate, these couplings are
>10 Hz, in agreement with a trans-trans axial arrange-
ment. The proposed stereochemistry is confirmed by
the NOEs between the H-atoms Ar-2′-6′ and 9ab of
F IGURE 2. Conformations of thuriferates and their ana-
logues 11 and 14.
compounds 12 and 14. The strong deshielding produced
on H7′ in compounds 11-14 is a consequence of its
proximity to the plane of the naphthalene system. The
results of molecular modeling, in agreement with the
more stable conformations deduced from NMR, are
shown in Figure 2.
Following our strategy for the preparation of podo-
phyllotoxin, the synthesis of 2,1-naphtho-podophyllotoxin
is straightforward from intermediate 7 (Scheme 5).
In agreement with the results described for isopodo-
phyllotoxone,21 the acidic epimerization at C8 yielded the
(19) San Feliciano, A.; Lo´pez, J . L.; Medarde, M.; Miguel del Corral,
J . M.; Pascual-Teresa, B.; Puebla, P. Tetrahedron 1988, 44, 7255.
(20) (a) Lo´pez, J . L.; Olmo, E.; Pascual-Teresa, B.; Merino, M.;
Mart´ın, S.; San Feliciano, A. Tetrahedron 1995, 51, 6343. (b) Lo´pez,
J . L.; Olmo, E.; Pascual-Teresa, B.; Merino, M.; San Feliciano, A.
Tetrahedron 1996, 52, 4903.
(21) (a) Medarde, M.; Ramos, A. C.; Caballero, E.; Lo´pez, J . L.;
Pela´ez-Lamamie´, R.; San Feliciano, A. Tetrahedron Lett. 1996, 37,
2663. (b) Miguel del Corral, J . M.; Gordaliza, M.; Lo´pez, J . L.; Olmo,
E.; Castro, M. A.; Lo´pez, M. L. Helv. Chim. Acta 1995, 78, 1793. (c)
J ackson, D. E.; Dewick, P. M. Phytochemistry 1985, 24, 2407.
J . Org. Chem, Vol. 68, No. 3, 2003 857

Madrigal et al.
SCHEME 5 a
a
i
Reagents and conditions: (a) AcOH, EtOH, 72 h, ∆; (b) LiAlH(tBuO)3/THF, 24 h, rt; (c) TBDMSTf, CH2Cl2, Pr2NEt, 4 h, 0 °C; (d)
LDA, THF, 15 min, -78 °C, then, AcOH; (e) Et3N‚3HF, CH3CN, 72 h, rt.
picropodophyllone stereochemistry for compound 15.
Upon reduction with the bulky tri-tert-butoxy lithium
aluminum hydride, a 2:1 mixture of epimeric alcohols 16
and 17 was obtained. Although these alcohols could not
be separated, the required tert-butyldimethylsilylation
was stereoselective toward 16, thus allowing the isolation
of the protected R-siloxy derivative 18 from its mixture
with the unprotected â-hydroxyderivative 17. Following
Kende’s methodology,22 deprotonation of 18 with lithium
hexamethyldisilazide followed by kinetic reprotonation
only produced the starting material, but a similar proce-
dure using lithium diisopropylamide yielded a mixture
of both stereoisomers at C-8′ (18 + 19). In this case a 4:1
ratio between the nontransformed “picro” isomer 18 and
the epimerized “podo” isomer 19 was observed (ratios
from 1.2:1 to 2:1 are usually described in the literature
for podophyllotoxins). The large coupling between H-8
and H-8′ (14.4 Hz) and NOEs on H-8′ upon irradiation
of H-7(â) are in agreement with the “podo” configuration
of 19.
Standard deprotection of compound 19 with TBAF
regenerated 16, with the more stable “picro” configura-
tion. The base character of fluoride ion in aprotic media
favors the epimerization at C-8′. To obtain the depro-
tected “podo” isomer, triethylamine trihydro fluoride was
used, yielding deprotected 20 with no detectable epimer-
ization to 16.
The synthesis of 2,1-naphthopodophyllotoxin, 20, con-
firmed the interest of this methodology. The most de-
manding step is the epimerization via deprotonation-
kinetic reprotonation, which in some instances was use-
less for the heterocyclic analogues of podophyllotoxin.12
Syn th esis fr om 2-(1-Na p h th yl)-1,3-d ith ia n e (21).
Once synthesis of the 2,1-naphtho analogues had been
completed, the preparation of the 1,2-naphtho derivatives
was attempted by the same procedure, using dithiane 21
as starting material. As depicted in Scheme 6, the
conjugate addition alkylation process yielded a mixture
of alcohols 22 and 23 and lactone 24.
The mixture of 22 and 23 could not be separated, and
its NMR spectra (1H and 13C) showed an unusual line
broadening in all the solvents assayed (CDCl3, DMSO-
d6, pyr-d5) in the temperature range from -7 to 60 °C.
The structures of 22 and 23 were confirmed by Raney
Ni reduction to hydroxy derivatives 25 and 26, analogues
of the natural products podorhizol and epi-podorhizol.23
The mixture of 22 + 23 was treated with trifluoroacetic
acid, yielding a mixture of two isomeric cyclization
products 27 and 28, which were isolated but could not
be identified directly because of spectral broadening. The
structural confirmation was completed by means of
chemical transformation in other derivatives, as dis-
cussed below. One possible explanation for the line
broadening seen in the NMR spectra is the presence of
several interconverting conformations of similar thermo-
dynamic stability, exchanging at intermediate rates on
the NMR time scale. Molecular modeling for these
compounds revealed the existence of two main confor-
mational clusters, arising from conformational changes
of the dithiane chair and the cycloheptane fused to the
naphthalene. Conformations of similar stabilities also
exist, due to rotation of the trimethoxyphenyl ring.
Accordingly, we decided to remove the no longer
required dithiane group, expecting a beneficial effect on
the NMR spectra. However, treatment of a 27 + 28
mixture following a standard procedure yielded com-
pound 29, instead of the deprotected ketones (Scheme 7).
Molecular modeling of compound 27 showed the close
proximity between position 2′ of the 3′,4′,5′-trimethox-
(22) Kende, A. S.; King, M. L.; Curran, D. P. J . Org. Chem. 1981,
46, 2826.
(23) Khun, M.; von Wartburg, A. Helv. Chim. Acta 1967, 1546.
858 J . Org. Chem., Vol. 68, No. 3, 2003

Naphthalene Analogues of Lignans
SCHEME 6 a
a
Reagents and conditions: (a) 1.6
M BuLi, THF, -78 °C, 45 min, then 5H-furan-2-one, THF, -78 °C, 3 h, then 3,4,5-
trimethoxybenzaldehyde, THF, TMEDA, -50 °C, 12 h; (b) Raney Ni, EtOH, 1 h, ∆; (c) TFA, CH2Cl2, 2 h, rt.
SCHEME 7 a
a
Reagents and conditions: (a) THF/H2O, HgO, 0 °C, then BF3‚OEt2, 24 h, rt; (b) Raney Ni, EtOH, 2 h, ∆; (c) Raney Ni, EtOH, 15 min,
∆; (d) Bu3SnH, AIBN, toluene, 72 h, 90 °C; (e) Me3O+BF4-, CH2Cl2, 10 h, rt.
yphenyl ring and the dithioketal position. The association
of the Hg2+ with the dithiane sulfur favors the cleavage
of the C-S bond24 and facilitates the attack of the
aromatic ring on the other side, explaining the unex-
pected ring closure.
Raney Ni reduction of 29 produced 30, whose structure
was unequivocally established by full spectroscopic char-
acterization. In the absence of key NOEs between the
lactone protons and those of the aromatic rings, the
disposition of the lactone toward the trimethoxyphenyl
ring was deduced from the strong deshielding effect on
both moieties upon addition of the europium shift reagent
Eu(fod)3.25 A similar deshielding effect was not observed
on the naphthalene resonances.
Transformation of 27 + 28 into the cyclized product
30 was also achieved with Raney Ni or tributyltin
hydride26 (TBTH, used to generate radicals from carbon-
heteroatom bonds).
Treatment of the mixture 27 + 28 with the alkylating
agent trimethyloxonium tetrafluoroborate (TFBTO),27
which is able to methylate the sulfur atoms, producing
the opening of the 1,3-dithiane moiety, generated ketone
31 and product 32. Compound 31 is formed by hydration
of the intermediate from the dithiane methylation and
opening. Compound 32 would result from elimination of
the methylated 1,3-dithiane. Compound 31 is the key
intermediate for the synthesis of thuriferic acid and
podophyllotoxin analogues, although its synthesis was
(24) Saigo, K.; Hashimoto, Y.; Kihara, N.; Hara, K.; Hasgawy, M.
Chem. Lett. 1990, 1097.
(25) (a) J iang J -L.; Li, A.-H.; J ang, S.-Y.; Chang, L.; Melman, N.;
Moro, S.; J i, X.-D.; Lobkovsky, E. B.; Clardy, J . C.; J acobson, K. A. J .
Med. Chem. 1999, 42, 3055. (b) Gu¨nther, H. NMR Spectroscopy; Wiley
& Sons: Chichester, UK, 2001; pp 431-435.
(26) (a) Anaya, J .; Barton, D. H. R.; Gero, S. D.; Grande, M.; Mart´ın,
N.; Tachdijian, C. Angew. Chem., Int. Ed. Engl. 1993, 32, 867. (b)
Yadav, V. K.; Fallis, A. G. Tetrahedron Lett. 1988, 29, 897.
(27) (a) Stahl, I. Synthesis 1981, 135. (b) Oishi, T.; Kamemoto, K.;
Ban, Y. Tetrahedron Lett. 1972, 13, 1085.
J . Org. Chem, Vol. 68, No. 3, 2003 859

Madrigal et al.
SCHEME 8 a
riferate analogue 41 by reaction with diazomethane
followed by acidic conditions. Comparing its 1H NMR
spectrum with that of compound 11 showed the 1,8-
naphtho derivative 41 to have deshielding of olefinic
methylene protons and higher coupling constants be-
tween 7′ and 8′ protons. The different conformation of
the cycloheptane ring explains these variations. The
general methodology for the preparation of podophyllo-
toxin analogues was also tried in this series. Accordingly,
trans ketone 31 was treated under acidic conditions, but
lactone ring opening was produced instead of epimeriza-
tion. The formation of compound 42 prevents the epimer-
ization at C-8, thus avoiding the synthesis of the podo-
phyllotoxin analogue in the 1,8-naphtho series.
As a final attempt to synthesize 1,2-naphtho analogues
of the podophyllotoxins from 1-naphthyl derivatives,
ketone 38 was used as the starting material. Considering
the possibility of a pericyclic reaction to circumvent the
lower reactivity of the naphthalene position 2 toward
electrophilic reagents, enol derivatives from 38 might
present the π-system for such a pericyclic reaction to take
place. The use of acetic anhydride as a solvent and a
reagent, for the formation of the enol acetate and the
pericyclic reaction, is very appealing. Treatment of 38
in refluxing acetic anhydride led to the phenanthrene
derivative 43, whose formation can be explained in terms
of the expected electrocyclic ring closure29 of the enolate
44, followed by dehydrogenation of the rearranged in-
termediate.
In conclusion, we have demonstrated the validity of our
methodology for the preparation of podophyllotoxin and
thuriferic acid analogues by the synthesis of 2,1-naphtho
analogues of lignans starting from naphthalene-2-car-
baldehyde. The same methodology, when used from
naphthalene-1-carbaldehyde, resulted in unexpected cy-
clizations to 1,8-naphtho-fused and -bridged products. A
representative compound of the 1,2-naphthalene series
was obtained by electrocyclic ring closure of a ketone
derived from 1-naphthyl starting materials.
a
Reagents and conditions: (a) KOH/MeOH (10%), 12 h, rt; (b)
Bu3SnH, AIBN, toluene, 72 h, 90 °C; (c) Me3O+BF4-, CH2Cl2,
24 h, rt.
preferably accomplished from 22 and 23, as will be
detailed below.
Reduction and acetylation of the mixture 27 + 28 prior
to the HgO and Raney Ni treatment had no effect on the
cyclization because the bridged diacetate 33 was pro-
duced. This compound is also directly obtained from 30.
An easy epimerization at the R-position of the strained
trans-fused lactone, from 28 to 27, explains the stereo-
chemistry of compounds 29, 30, and 33; obtained as
single diastereomers.
To check whether the formation of bridged compounds
is produced from any compound with the structural moie-
ties of 27 and 28 or whether a specific conformation is
needed for such a cyclization to take place, we pre-
pared compound 34. This derivative of the 2,1-naphtho
series was obtained by epimerization of compound 6
(Scheme 8).
If a specific conformation is not strictly required, com-
pounds with the same groupings but with lower proxim-
ity between the 3′,4′,5′-trimethoxyphenyl ring and the
1,3-dithiane would lead to similar bridged derivatives.
Compound 34 was subjected to radical (TBTH) and cat-
ionic (TFBTO) conditions. In both cases, unreacted mate-
rial was recovered, along with deprotected ketone 15 in
the first case and the rearranged product 35 in the sec-
ond. Compound 35 shows a new bond between former
positions 2′ of the 3′,4′,5′-trimethoxyphenyl ring and 2
of the 1,3-dithiane moiety, but we have no mechanistic
explanation for this transformation. These results dem-
onstrate that the easy cyclizations of the 1,8-naphthalene
series are strongly induced by their particular conforma-
tion.
Ketone 31, required for the synthesis of thuriferic acid
analogues, was alternatively prepared by cyclization of
keto-lactones 36 and 37 (Scheme 9). TFA treatment of
36 + 37 gave 38 as the major reaction product and ketone
31 as the minor one. Due to the deactivation of the
naphthalene ring by the conjugated keto group, dehydra-
tion is a competitive reaction and anhydropodorhizol28
analogue 38 can be obtained.
Exp er im en ta l Section
Gen er a l Meth od s. All chemicals were reagent grade and
used as purchased. All moisture-sensitive reactions were
performed under an inert atmosphere of argon using distilled
dry solvents. Reactions were monitored by TLC analysis using
silica gel 60 F254 thin layer plates. Flash chromatography was
carried out on silica gel 60 (230-400 mesh). Melting points
were determined in capillary tubes and are uncorrected. IR
spectra were recorded in a range of 4000-600 cm-1. H NMR
1
(400 MHz) and 13C NMR (100 MHz) were acquired in CDCl3
or DMSO-d6 as a solvent; all chemical shifts (δ) are given in
parts per million (ppm) relative to tetramethylsilane, and all
coupling constants (J ) are in hertz. Mass spectra were recorded
by electronic impact or chemical ionization. For FABMS
analyses, a VG-TS 250 apparatus (70 eV) was used. Elemental
analyses were recorded in a 2400 CHN apparatus. Systematic
conformational searches using Monte Carlo and MM2 as
molecular force field and clustering of the resulting conforma-
tions were performed under Macromodel and Xcluster v.5.1
on Silicon Graphics workstations.
2-Na p h th a len e Ser ies: Con ju ga te Ad d ition -Alk yla -
tion Rea ction . n-BuLi (1.6 M in hexane) (9.6 mL, 15.4 mmol)
(28) Turabelidze, D. G.; Kikaya, G. A.; Kemertelidze, E. P.; Wulfson,
N. S. Bioorg. Chim. 1982, 8, 695.
(29) Anjaneyulu, A. S. R.; Rao, V. K.; Rao, A. M.; Row, L. R. Curr.
Sci. 1974, 43, 542.
Treatment of 31 with base produced a mixture of 39
and 40, which were transformed into the methyl thu-
860 J . Org. Chem., Vol. 68, No. 3, 2003

Naphthalene Analogues of Lignans
SCHEME 9 a
a
Reagents and conditions: (a) THF/H2O, HgO, 0 °C, then BF3‚OEt2, 24 h, rt; (b) TFA, CH2Cl2, 24 h, rt; (c) KOH/MeOH (1%), 15 h, rt;
(d) AcOH, EtOH, 48 h, ∆; (e) Ac2O exc, 7 h, ∆; (f) excess CH2N2/ether, then p-TsOH, 8 h, ∆.
was added to a solution of 2-(2-naphthyl)-1,3-dithiane (1, 3.4
g, 14 mmol) in dry THF (140 mL) at -78 °C under argon. After
45 min, a solution of 5H-furan-2-one (0.9 mL, 14 mmol) in dry
THF (14 mL) was added dropwise. The reaction mixture was
stirred at -78 °C for 3 h and then allowed to warm to -50 °C.
A solution of 3,4,5-trimethoxybenzaldehyde (4.1 g, 21 mmol)
in dry THF and TMEDA (4.2 mL, 28 mmol) were successively
added. The mixture was stirred for 12 h at -50 °C, and then
the reaction was quenched by addition of NH4Cl (concentrated
solution). After the usual workup and flash chromatography
(7:3 hexane/ethyl acetate) afforded 4 (0.8 g, 17%), 2 (2.9 g, 40%)
and 3 (1.9 g, 26%) were isolated.
Cycliza tion Rea ction . TFA (13 mL) was added dropwise
to a solution of 2 and 3 (1.4 g, 2.7 mmol) in CH2Cl2 (27 mL).
The reaction mixture was stirred for 24 h at room temperature,
and then the reaction was quenched with NaHCO3 (concen-
trated solution). After the usual workup and crystallization
(hexane/ethyl acetate) of the crude product, a 2:1 mixture (0.9
g, 66%) of 5 and 6 was obtained. This mixture was separated
by flash chromatography (4:3 Hex/AcOEt) yielding 5 (0.52 g,
38%) and 6 (0.23 g, 17%).
Dep r otection Rea ction . A solution of 5 and 6 (1.5 g, 2.9
mmol) in 60 mL of 85:15 THF/H2O was added to a suspension
of HgO (1.25 g, 5.8 mmol) in 85:15 THF/H2O at 0 °C under
argon followed by BF3‚OEt2 (0.7 mL, 5.8 mmol). The reaction
mixture was stirred for 24 h at room temperature, and then
CH2Cl2 (20 mL) was added and the precipitate filtered.
Crystallization (from hexane/ethyl acetate) of the organic
phase afforded a 2:1 mixture of 7 and 8 (1 g, 79%), which were
isolated by chromatography (8:2 hexane/ethyl acetate).
(()-(7aS,10aS,11R)-11-(3,4,5-Tr im eth oxyph en yl)-7,7a,8,-
10,10a ,11-h exa h yd r on a p h t h o[1,2-f]isob en zofu r a n -7,10-
d ion e (7). IR (CHCl3): 1775; 1690; 1596. 1H NMR (CDCl3):
60.8; 65.9; 106.0 (2C); 121.7; 126.9; 127.7; 128.5; 128.9; 129.1;
131.6; 132.2; 136.6 (2C); 139.4; 142.7; 153.2 (2C); 173.3; 194.6.
MS (FAB) (m/z): 418 (M+, 100). Anal. Calcd for C25H22O6: C,
71.76; H, 5.30. Found: C, 71.41; H, 5.00.
(()-(7aR,10aR,11R)-11-(3,4,5-Tr im eth oxyph en yl)-7,7a,8,-
10,10a ,11-h exa h yd r on a p h t h o[1,2-f]isob en zofu r a n -7,10-
d ion e (8). Mp: 224 °C (from MeOH). IR (KBr): 1779; 1695;
1590; 1450. 1H NMR (CDCl3): 3.37 (dd, 1H, J 1 ) 4.2, J 2
)
15.7); 3.65 (br s, 6H); 3.67 (m, 1H); 3.80 (s, 3H); 4.47 (dd, 1H,
J 1 ) 9.4, J 2 ) 10.3); 4.60 (dd, 1H, J 1 ) 7.6, J 2 ) 9.4); 5.58 (d,
1H, J ) 4.2); 6.40 (br s, 2H); 7.51 (t, 1H, J ) 8.4); 7.61 (t, 1H,
J ) 8.4); 7.91 (d, 2H J ) 8.4); 7.94 (d, 1H, J ) 8.7); 8.22 (d,
1H, J ) 8.7). 13C NMR (CDCl3): 41.6; 43.8; 46.9; 56.2 (2C);
60,7; 67.0; 107.3 (2C); 122.2; 126.0; 127.7; 128.8; 129.0; 129.1;
130.9 (2C); 131.6; 136.4, 137.6; 143.0; 153.2 (2C); 173.1; 194.3.
MS (FAB) (m/z): 418 (M+, 20). Anal. Calcd for C25H22O6: C,
71.76; H, 5.30. Found: C, 71.73; H, 5.24.
La ct on e-Op en in g R ea ct ion . Compound 7 (380 mg, 0.9
mmol) was treated with a solution of KOH in MeOH (1%) for
1.5 h at room temperature. Then, HCl (2 N) was added and
the reaction worked-up, affording 250 mg of a mixture of 10
and 9.
Ester ifica tion Rea ction . A mixture of 10 and 9 (1.7 g)
was treated with an excess of a saturated solution of CH2N2
in ether for 5 min. The crude product was purified by
chromatography (1:1 hexane/ethyl acetate) affording a 3:1
mixture of 12 and 11 (890 mg, 51%) and 13 (400 mg, 21%).
Methyl esters 11 and 12 were isolated by further chromatog-
raphy.
(()-Meth yl (3S,4R)-2-Meth ylen -1-oxo-4-(3,4,5-tr im eth -
oxyp h e n yl)-1,2,3,4-t e t r a h yd r op h e n a n t h r e n e -3-ca r b -
oxyla te (11). Mp: 218 °C (from MeOH). IR (KBr): 1732; 1678;
1589. 1H NMR (CDCl3): 3.51 (s, 3H); 3.68 (s, 6H); 3.75 (s, 3H);
4.04 (s, 1H); 5.41 (s, 1H); 5.58 (s, 1H); 6.27 (s, 2H); 6.43 (s,
1H); 7.50 (t, 1H, J ) 8.4); 7.87 (t, 1H, J ) 8.4); 7.89 (d, 1H, J
) 8.4); 8.02 (d, 1H, J ) 8.4); 8.28 (d, 1H, J ) 8.4). 13C NMR
(CDCl3): 44.8; 52.6; 55.9; 56.0 (2C); 60.7; 105.1 (2C); 122.9;
125.4; 126.7; 126.8; 127.2; 128.5; 128.7; 130.5; 131.0; 136.3;
3.07 (dd, 1H, J 1 ) 9.8, J 2 ) 10.2); 3.50 (dd, 1H, J 1 ) 6.4, J 2
)
10.2); 3.65 (br s, 6H); 3.76 (s, 3H); 4.44-4.66 (m, 2H); 5.14 (d,
1H, J ) 10.2); 6.40 (br s, 2H); 7.33 (t, 1H, J ) 6.9); 7.50 (t,
1H, J ) 6.9); 7.81-7.94 (m, 2H); 7.83 (d, 1H, J ) 8.4); 8.30 (d,
1H, J ) 8.4). 13C NMR (CDCl3): 46.8; 47.6; 48.6; 56.2 (2C);
J . Org. Chem, Vol. 68, No. 3, 2003 861

Madrigal et al.
136.7; 136.9; 137.6; 140.0; 153.3 (2C); 172.1; 186.1. MS (FAB)
(m/z): 433 (M+, 100). Anal. Calcd for C26H24O6: C, 72.21; H,
5.59. Found: C, 71.97; H, 5.48.
5.03 (d, 1H, J ) 6.6); 5.50 (s, 1H); 6.25 (s, 2H); 7.30-7.90 (m,
4H); 7.44 (d, 1H, J ) 8.4); 7.83 (d, 1H, J ) 8.4). 13C NMR
(CDCl3): 40.0; 40.4; 47.1; 56.1 (2C); 60.8; 71.7; 72.0; 104.8 (2C);
124.5; 125.7; 126.3; 127.0; 128.5; 128.6; 129.0; 131.0; 133.6;
134.2; 136.8; 139.9; 153.6 (2C); 177.2. Anal. Calcd for
(()-Meth yl (2S,3S,4R)-2-Meth oxym eth yl-1-oxo-4-(3,4,5-
t r im et h oxyp h en yl)-1,2,3,4-t et r a h yd r op h en a n t h r en e-3-
ca r boxyla te (12). IR (CHCl3): 1733; 1676. 1H NMR (CDCl3):
3.18 (ddd, 1H, J 1 ) 4.7, J 2 ) 5.4, J 3 ) 8.3); 3.29 (s, 3H); 3.57
(s, 3H); 3.67 (s, 6H); 3.73 (dd, 1H, J 1 ) 8.3, J 2 ) 9.9); 3.75 (dd,
1H, J 1 ) 1.8, J 2 ) 4.7); 3.80 (s, 3H); 4.12 (dd, 1H, J 1 ) 5.4, J 2
) 9.9); 5.38 (d, 1H, J ) 1.8); 6.28 (s, 2H); 7.47 (t, 1H, J ) 8.6);
7.54 (t, 1H, J ) 8.6); 7.80 (d, 1H, J ) 8.6); 7.83 (d, 1H, J )
8.6); 7.90 (d, 1H, J ) 8.6); 8.24 (d, 1H, J ) 8.6). 13C NMR
(CDCl3): 42.6; 44.0; 49.3; 51.5; 55.4 (2C); 58.1; 60.0; 69.1; 104.8
(2C); 121.4; 124.8; 126.4; 127.5; 127.9; 128.1; 129.8; 130.3;
135.5; 136.0; 136.4; 137.3; 152.8 (2C); 172.0; 195.1. MS (FAB)
(m/z): 465 (M+ + 1, 30). Anal. Calcd for C27H28O7: C, 63.85;
H, 5.74. Found: C, 63.59; H, 5.48.
C
25H24O6: C, 71.41; H, 5.75. Found: C, 71.40; H, 5.62.
P r otection Rea ction . To a solution of 16 and 17 (125 mg,
i
0.3 mmol) in CH2Cl2 (5.9 mL) and Pr2NEt (0.3 mL, 1.7 mmol),
at 0 °C under argon, TBDMSTf (0.3 mL, 1.2 mmol) was added
dropwise. After 4 h, a solution of oxalic acid was added until
acidic pH was reached. Workup and flash chromatography (2:1
hexane/ethyl acetate) of the crude product afforded 18 (80 mg,
50%) and 17 (26 mg, 21%).
Ba sic Ep im er iza tion . A solution of 18 (75 mg, 0.14 mmol)
in THF (2.8 mL) under argon was cooled to -78 °C, and LDA
(0.28 mmol) was added. The solution was maintained at this
temperature for 15 min, and then glacial acetic acid (40 µL,
0.7 mmol) in THF (4.3 M) was added. Extraction with ethyl
acetate and flash chromatography (2:1 hexane/ethyl acetate)
of the crude product afforded 19 (11 mg, 15%) and 18 (60 mg,
80%).
Dep r otection Rea ction s. To a solution of 19 (20 mg, 0.04
mmol) in CH3CN (1.8 mL) under argon was added TBAF (69
mg, 0.22 mmol) and the reaction maintained for 48 h at room
temperature. After the usual work up, alcohol 16 (10 mg, 60%)
was obtained as a pure product.
By treatment of 12 (86 mg, 0.2 mmol) with p-TsOH (38 mg,
0.2 mmol) in benzene at reflux for 7 h, compound 11 (86 mg,
100%) was obtained as a pure product.
Ch lor in a tion Rea ction . By treatment of 11 (70 mg, 0.16
mmol) in CH2Cl2 (5 mL) with a dry stream of HCl for 2 h
followed by argon to eliminate the excess of reagent, the chloro
derivative 14 (60 mg, 80%) was obtained in pure form.
Acid ic Ep im er iza tion . To a solution of 7 (1.8 g, 4.3 mmol)
in ethanol (70 mL) was added glacial acetic acid (140 mL). The
reaction mixture was refluxed for 72 h and then allowed to
cool to room temperature, and the reaction was quenched with
a concentrated solution of NaHCO3. After the usual workup
and flash chromatography (2:3 hexane/ethyl acetate), 1.5 g of
15 (83%) was isolated.
To a solution of 19 (28 mg, 0.05 mmol) in CH3CN (2.6 mL)
under argon was added a solution of Et3N‚3HF (2.0 M) in CH3-
CN added. The reaction mixture was maintained at room
temperature for 72 h and then evaporated in a vacuum
affording 20 (18 mg, 85%).
(()-(7aR,10aS,11R)-11-(3,4,5-Tr im eth oxyph en yl)-7,7a,8,-
(()-(7R,7a R,10a R,11R)-7-H yd r oxy-11-(3,4,5-t r im et h -
oxyp h en yl)-7,7a ,8,10,10a ,11-h exa h yd r on a p h th o[1,2-f]iso-
b en zofu r a n -10-on e (20). Mp: 240 °C (from ether). IR
10,10a ,11-h exa h yd r on a p h t h o[1,2-f]isob en zofu r a n -7,10-
1
d ion e (15). IR (CHCl3): 1774; 1673; 1591. H NMR (CDCl3):
3.40 (dd, 1H, J 1 ) 5.9, J 2 ) 8.0); 3.53 (dd, 1H, J 1 ) 1.8, J 2
8.0); 3.69 (s, 6H); 3.76 (s, 3H); 4.42 (dd, 1H, J 1 ) 5.9, J 2
)
)
1
(KBr): 3476; 1773. H NMR (CDCl3): 2.91(dd, 1H, J 1 ) 4.4,
J 2 ) 14.4); 2.97 (m, 1H); 3.67 (s, 6H); 3.80 (s, 3H); 4.15 (t, 1H,
J ) 8.4); 4.68 (dd, 1H, J 1 ) 6.8, J 2 ) 8.4); 5.04 (d, 1H, J )
8.4); 5.30 (d, 1H, J ) 4.4); 6.45 (br s, 2H); 7.41 (t, 1H, J ) 8.4);
7.46 (t, 1H, J ) 8.4); 7.76 (br d, 1H, J ) 8.4); 7.83 (d, 1H, J )
8.4); 7.85 (br d, 1H, J ) 8.4); 7.89 (d, 1H, J ) 8.4). 13C NMR
(CDCl3): 40.7; 41.2; 45.5; 56.2 (2C); 60.7; 71.5; 73.4; 108.8 (2C);
124.1; 124.7; 126.2; 127.1; 128.9; 129.0; 131.5, 133.0; 133.3
(2C); 134.7; 136.9; 152.8 (2C); 174.5. MS (FAB) (m/z): 420 (M+,
10). Anal. Calcd for C25H24O6: C, 71.41; H, 5.75. Found: C,
71.04; H, 5.68.
9.2); 4.86 (d, 1H, J ) 9.2); 5.53 (s, 1H); 6.29 (s, 2H); 7.53 (t,
1H, J ) 8.6); 7.60 (t, 1H, J ) 8.6); 7.85 (d, 1H, J ) 8.6); 7.89
(d, 1H, J ) 8.6); 8.10 (d, 1H, J ) 8.6); 8.13 (d, 1H, J ) 8.6).
13C NMR (CDCl3): 39.4; 43.2; 47.1; 56.1 (2C); 60.7; 70.6; 104.4
(2C); 122.2; 125.4; 127.8; 128.5, 129.0; 129.2; 130.1; 130.9;
136.6; 137.2; 137.6; 140.7; 153.8 (2C); 175.5, 195.9. MS (FAB)
(m/z): 418 (M+, 100). Anal. Calcd for C25H22O6: C, 71.76; H,
5.30. Found: C, 71.68; H, 5.21.
R ed u ct ion R ea ct ion . Ketone 15 (250 mg, 0.6 mmol) in
THF (60 mL) was slowly added to LiAlH(tBuO)3 (0.6 g, 2.4
mmol) in THF (3 mL) and allowed to react at room tempera-
ture for 24 h. The reaction was quenched with a saturated
NH4Cl solution and acidified with aqueous oxalic acid (satu-
rated solution). Flash chromatography (3:2 hexane/ethyl ac-
etate) of the crude product afforded a 2:1 mixture of compounds
16 and 17 (125 mg, 50%).
(()-(7R,7a R,10a S,11R)-7-H yd r oxy-11-(3,4,5-t r im e t h -
oxyp h en yl)-7,7a ,8,10,10a ,11-h exa h yd r on a p h t h o[1,2-f]-
isob en zofu r a n -10-on e (16). Data were taken from the
product isolated in the TBAF deprotection reaction. IR
(CHCl3): 3480; 1770; 1590. 1H NMR (CDCl3): 3.10 (m, 1H);
3.53 (dd, 1H, J 1 ) 1.8, J 2 ) 8.4); 3.68 (s, 6H); 3.78 (s, 3H);
4.42 (dd, 1H, J 1 ) 5.8, J 2 ) 9.2); 4.86 (d, 1H, J ) 9.2); 4.90 (d,
1H, J ) 4.4); 5.53 (s, 1H); 6.29 (s, 2H); 7.41-7.56 (m, 2H);
7.55 (d, 1H, J ) 8.0); 7.74-7.95 (m, 2H); 7.85 (d, 1H, J ) 8.0).
13C NMR (CDCl3): 38.1; 45.2; 55.2; 56.1; 60.7; 61.1; 69.9; 105.4
(2C); 122.3; 125.4; 127.8; 128.5; 128.7; 128.9; 130.7; 130.9;
136.7; 137.2; 137.6; 140.0; 153.5 (2C); 172.4. MS (FAB) (m/z):
420 (M+, 10). Anal. Calcd for C25H24O6: C, 71.41; H, 5.75.
Found: C, 71.18; H, 5.58.
1-Na p h th a len e Ser ies: Con ju ga te Ad d ition -Alk yla -
tion Rea ction . By the same procedure used for the 2-naph-
thalene series, from 2-(1-naphthyl)-1,3-dithiane (21, 3.6 g, 15
mmol; in 150 mL of dry THF), n-BuLi (1.6 M in hexane; 10.3
mL, 16.5 mmol), 5H-furan-2-one (0.9 mL, 15 mmol; in 15 mL
of dry THF), and 3,4,5-trimethoxybenzaldehyde (4.4 g, 23
mmol; in dry THF and 4.5 mL, 30 mmol of TMEDA) were
isolated 22 and 23 (5.0 g, 64%) and 24 (0.6 g, 11%) after
chromatography (7:3 hexane/ethyl acetate).
Cycliza tion Rea ction . By the same procedure used for the
2-naphthalene series, from a mixture of 22 and 23 (1.0 g, 1.9
mmol) in CH2Cl2 (9.5 mL) with TFA (9.5 mL) were isolated
28 (485 mg, 49%) and 27 (425 mg, 24%) after chromatography
(99:1 CH2Cl2/MeOH).
Tr ea tm en t w ith Ra n ey Ni. A mixture of 22 and 23 (20
mg, 0.038 mmol) in EtOH (5 mL) was treated with an excess
of Raney Ni and stirred at reflux for 1 h. The crude product
was purified by chromatography (99:1 CH2Cl2/MeOH) affording
25 (10 mg, 62%) and 26 (2 mg, 13%).
A mixture of 28 and 27 (40 mg, 0.08 mmol) in EtOH (8 mL)
was treated with an excess of Raney Ni and stirred at reflux
for 15 min. The filtrate was extracted with ethyl acetate and
purified by chromatography (8:2 hexane/ethyl acetate) afford-
ing 30 (18 mg, 56%).
(()-(7S ,7a R ,10a S ,11R )-7-H yd r oxy-11-(3,4,5-t r im e t h -
oxyp h en yl)-7,7a ,8,10,10a ,11-h exa h yd r on a p h th o[1,2-f]iso-
ben zofu r a n -10-on e (17). Data were taken from the product
isolated in the protection reaction. IR (CHCl3): 3469; 1760;
1591. 1H NMR (CDCl3): 3.50 (m, 1H); 3.64 (s, 6H); 3.70 (m,
1H); 3.79 (s, 3H); 4.25 (t, 1H, J ) 5.0); 4.33 (t, 1H, J ) 8.4);
Compound 29 (see synthesis below, 50 mg, 0.1 mmol) in
EtOH (10 mL) was treated with an excess of Raney Ni and
862 J . Org. Chem., Vol. 68, No. 3, 2003

Naphthalene Analogues of Lignans
stirred at reflux for 2 h. By the same procedure described
above, 30 (32 mg, 81%) was isolated
compound (20 mmol, 0.03 mmol) in EtOH (4 mL) was treated
with an excess of Raney Ni, yielding 33 (15 mg, 90%).
To a solution of 30 (29 mg, 0.05 mmol) in 5 mL of dry THF
was added 29 mg of LiAlH4 (0.08 mmol) in dry THF. After 1
h, the reaction mixture was filtered affording 15 mg (73%) of
the corresponding diol. This reaction product was treated with
an excess of acetic anhydride in pyridine for 7 h. After the
usual workup, 33 (18 mg, 73%) was obtained.
Tr ea tm en t w ith KOH/MeOH. To a 2:1 mixture of 5 and
6 (630 mg, 1.2 mmol) was added 12 mL of KOH/MeOH (10%).
After 12 h, 2 N HCl was added and the white precipitate
filtered and crystallized in MeOH, affording a 2:1 mixture of
5 and 34, which were then separated by chromatography (7:3
hexane/ethyl acetate), yielding 34 (150 mg, 25%).
(()-(7S ,7a R ,10a S ,11R )-7,11-(3,4,5-T r im e t h o x y -1,2-
p h e n yle n e )-7,7a ,10a ,11-t e t r a h yd r o-8H -10H -n a p h t h o-
[1′,8a ′,8′:4,5,6]cycloh ep ta [c]fu r a n -8-on e (30). IR (CHCl3):
1
1765; 1478; 1125. H NMR (CDCl3): 3.35 (m, 1H); 3.40-3.87
(dd, 1H, J 1 ) 6.1, J 2 ) 11.9); 3.82 (s, 6H); 3.85 (s, 3H); 3.93
(dd, 1H, J 1 ) 4.7, J 2 ) 9.5); 4.44 (t, 1H, J ) 4.7); 4.56 (d, 1H,
J ) 6.1); 4.70 (d, 1H, J ) 5.9); 6.71 (s, 1H); 7.33 (t, 1H, J )
8.1); 7.34 (t, 1H, J ) 8.1); 7.38 (d, 1H, J ) 8.1); 7.43 (d, 1H, J
) 8.1); 7.67 (d, 1H, J ) 8.1); 7.68(d, 1H, J ) 8.1). 13C NMR
(CDCl3): 40.7; 43.5; 47.0; 50.1; 56.1; 60.9; 61.4; 69.5; 106.0;
125.4; 125.5; 125.9; 127.1 (2C); 128.6; 128.7; 129.2; 135.3;
135.6; 135.8; 136.0; 141.1; 149.8; 152.4; 176.4. MS (FAB) (m/
z): 403 (M+ + 1, 100). Anal. Calcd for C25H22O5: C, 74.61; H,
5.51. Found: C, 74.49; H, 5.50.
Tr ea tm en t w ith Bu 3Sn H. A solution of Bu3SnH (166 µL)
and AIBN (10 mg) in 30 mL of toluene was added to a solution
of 34 (100 mg, 0.2 mmol) in dry toluene (70 mL) at 80-90 °C.
The reaction was maintained at reflux for 72 h. The crude
product (90 mg) was chromatographed (6:4 hexane/ethyl
acetate), yielding 15 (45 mg, 54%) and 34 (30 mg, 30%).
Dep r otection Rea ction . By the same procedure used for
the 2-naphthalene series, from 27 and 28 (3 g, 5.8 mmol; in
100 mL of 85:15 THF/H2O), HgO (2.5 g, 11.6 mmol; in 18 mL
of 85:15 THF/H2O), and BF3‚OEt2 (1.3 mL, 10.7 mmol) was
obtained 29 (1.5 g, 51%).
Tr ea tm en t w ith Me3O+BF 4-. Me3O+BF4 (29 mg, 0.2
-
mmol) was added to a solution of 34 (90 mg, 0.18 mmol) in 25
mL of anhydrous CH2Cl2. The reaction mixture was stirred
for 24 h at room temperature, and the reaction was quenched
with water; the mixture was then extracted with CH2Cl2,
affording a mixture of 34 (40 mg, 44%) and 35 (20 mg, 28%).
5,6,7-Tr im et h oxy-4-(2-n a p h t h yl)-3H -n a p h t h o[2,3-c]-
fu r a n -1-on e (35). IR (CHCl3): 3417; 1766; 1589. 1H NMR
(CDCl3): 3.18 (s, 3H); 3.91 (s, 3H); 4.05 (s, 3H); 4.94 (d, 1H, J
(()-(7R,7a R,10a S,11R)-7,11-(3,4,5-Tr im eth oxy-1,2-p h e-
n ylen e)-11-(3-m er ca p top r op ylth io)-7,7a ,10a ,11-tetr a h y-
d r o-8H-10H-n a p h th o[1′,8a ′,8′:4,5,6]cycloh ep ta [c]fu r a n -8-
on e (29). IR (CHCl3): 1768; 1596. 1H NMR (CDCl3): 2.18 (m,
2H); 2.65 (m, 2H); 2.77 (m, 2H); 3.52 (s, 3H); 3.78 (s, 3H); 3.79
(s, 3H); 3.80 (m, 1H); 3.40-3.87 (m, 2H); 4.50 (m, 1H); 4.51
(d, 1H, J ) 6.0); 6.72 (s, 1H); 7.26-7.44 (m, 4H); 7.69 (d, 1H,
J ) 8.0); 8.00 (d, 1H, J ) 7.3). 13C NMR (CDCl3): 29.0; 33.5;
34.5; 45.5; 46.2; 51.2; 56.0; 59.4; 61.3; 62.0; 70.6; 107.2; 123.7;
125.1; 125.9 (2C); 127.6; 128.5; 129.4; 129.8; 135.6 (2C); 135.9;
136.2; 142.4; 151.8; 152.7; 176.6. MS (FAB) (m/z): 508 (M+,
10). Anal. Calcd for C28H28O5S2: C, 66.12; H, 5.56. Found: C,
65.94; H, 5.36.
) 14.8); 5.15 (d, 1H, J ) 14.8); 7.20 (s, 1H); 7.43 (dd, 1H, J 1
)
1.6, J 2 ) 8.2); 7.54 (m, 1H); 7.55 (m, 1H); 7.75 (s, 1H); 7.85
(m, 1H); 7.94 (m, 2H); 8.37 (s, 1H). 13C NMR (CDCl3): 56.1;
60.7; 61.1; 70.0; 104.5; 122.4; 125.1; 125.6; 126.1 (2C); 126.4;
127.1; 127.3; 127.9 (2C); 131.9; 132.0; 132.3; 132.9; 137.2;
139.0; 144.9; 149.6; 153.5; 171.3. MS (FAB) (m/z): 401 (M+
1, 30). Anal. Calcd for C25H20O5: C, 74.99; H, 5.03. Found: C,
74.83; H, 4.94.
+
Tr ea tm en t w ith Me3O+BF 4-. A mixture of 27 and 28 (100
mg, 0.2 mmol) in 20 mL of CH2Cl2 was treated with Me3O+BF4
-
(89 mg, 0.6 mmol). The reaction was stirred for 10 h at room
temperature. The crude product was purified by chromatog-
raphy (8:2 hexane/ethyl acetate) affording 31 (24 mg, 29%) and
32 (20 mg, 25%).
Dep r otection Rea ction . By the usual procedure, 22 and
23 (3 g, 5.8 mmol; in 100 mL of 85:15 THF/H2O) were treated
with HgO (2.25 g, 10.4 mmol; in 18 mL of THF/H2O 85:15)
and BF3‚OEt2 (1.3 mL, 10.7 mmol) affording, after chroma-
tography (7:3 hexane/ethyl acetate), a mixture of 36 and 37
(2.02 g, 79%) that was used in the next reaction without
further purification.
Cycliza tion Rea ction . By the usual procedure, a mixture
of 36 and 37 (390 mg, 0.89 mmol; in 2 mL of CH2Cl2) was
treated with TFA (2 mL), followed by chromatography (7:3
hexane/ethyl acetate), yielding 31 (120 mg, 32%) and 38 (250
mg, 67%).
La cton e-Op en in g Rea ction . By the usual procedure, from
31 (50 mg, 0,12 mmol), 40 mg of a mixture of 39 and 40 was
obtained and used in the next reaction without further
purification.
Ester ifica tion Rea ction . A mixture of 39 and 40 (40 mg)
was treated with an excess of a saturated solution of CH2N2
in ether for 5 min. The solvent was evaporated, and the crude
product was refluxed in benzene with p-TsOH for 8 h, affording
41 (30 mg, 73%).
(()-Meth yl (7R,8S)-9-Meth ylen e-10-oxo-7-(3,4,5-tr im eth -
oxyp h e n yl)-7,8,9,10-t e t r a h yd r o-cycloh e p t a [d ,e]n a p h -
th a len e-8-ca r boxyla te (41). IR (CHCl3): 1738; 1591. 1H
NMR (CDCl3): 3.30 (s, 3H); 3.63 (s, 6H); 3.87 (s, 3H); 4.40 (d,
1H, J ) 7.8); 5.22 (d, 1H, J ) 7.8); 6.03 (s, 1H); 6.24 (s, 2H);
6.66 (s, 1H); 7.41-7.60 (m, 4H); 7.87 (m, 1H); 8.07 (m, 1H).
13C NMR (CDCl3): 52.1; 52.5; 54.2; 56.1 (2C); 60.9; 105.9 (2C);
125.5; 125.9; 126.4; 126.8; 128.8; 129.3; 131.2; 131.4; 134.2;
134.4; 135.4; 137.0; 137.5; 144.0; 153.3 (2C); 171.9; 185.0. Anal.
Calcd for C26H24O6: C, 72.21; H, 5.59. Found: C, 72.13; H,
5.41.
(()-(7 R ,7 a S ,1 0 a S )-7 -(3 ,4 ,5 -T r i m e t h o x y p h e n y l )-
7,8,10a ,11-t et r a h yd r o-7H ,10H -n a p h t h o[1′,8a ′,8′:4,5,6]cy-
cloh ep ta [c]fu r a n -8,11-d ion e (31). IR (CHCl3): 1770; 1682;
1590. 1H NMR (CDCl3): 3.30 (dd, 1H, J 1 ) 6.2, J 2 ) 14.6);
3.54 (s, 6H); 3.68 (s, 3H); 4.15 (m, 1H); 4.40 (dd, 1H, J 1 ) 7.3,
J 2 ) 9.5); 4.89 (t, 1H, J ) 9.5); 5.07 (d, 1H, J ) 6.2); 6.08 (s,
2H); 7.46-7.66 (m, 3H); 7.90 (d, 1H, J ) 8.0); 8.10 (d, 1H, J )
8.4); 8.39 (d, 1H, J ) 7.3). 13C NMR (CDCl3): 51.4; 51.9; 52.5;
55.7 (2C); 60.6; 65.3; 103.8 (2C); 124.8; 130.7 (2C); 133.5, 135.0;
135.5; 135.6; 135.7; 136.4 (2C); 137.5; 141.7; 153.1 (2C); 175.7;
194.7. MS (m/z): 419 (M+ + 1, 5). Anal. Calcd for C25H22O6:
C, 71.76; H, 5.30. Found: C, 71.80; H, 5.32.
7 -( 3 ,4 ,5 -T r i m e t h o x y p h e n y l ) -8 H ,1 0 H -n a p h t h o -
[1′,8a ′,8′:4,5,6]cycloh ep ta [c]fu r a n -8-on e (32). IR (CHCl3):
1761; 1584. 1H NMR (CDCl3): 3.48-3.95 (m, 2H); 3.88 (s, 6H);
3.99 (s, 3H); 5.54 (s, 2H); 6.62 (s, 2H); 7.45-7.50 (m, 2H); 7.67-
7-78 (m, 2H); 7.90 (m, 2H); 8.80 (s, 1H). 13C NMR (CDCl3):
56.2 (2C); 61.1; 68.5; 107.6 (2C); 115.3; 123.6; 124.8; 126.9;
128.0; 128.9; 129.6; 129.7; 130.2; 130.4; 132.8; 134.7; 138.0;
139.0; 141.5; 142.2; 153.0 (2C); 170.0. MS (FAB) (m/z): 401
(M+ + 1, 5). Anal. Calcd for C25H20O5: C, 74.99; H, 5.03.
Found: C, 74.66; H, 4.89.
Dia ceta te 33. A solution of 28 (70 mg, 0.14 mmol) in 20
mL of dry THF was added to a suspension of LiAlH4 (100 mg,
2.8 mmol) in dry THF. After 1 h at room temperature, the
reaction mixture was filtered affording 70 mg (98%) of the diol,
which was treated with an excess of acetic anhydride in
pyridine. The resulting diacetate (60 mg, 0.1 mmol) in 2 mL
of 85:15 THF/H2O was deprotected with HgO (32 mg, 0.15
mmol; in 2 mL of 85:15 THF/H2O) followed by BF3‚OEt2 (19
µL, 0.15 mmol) yielding, after chromatography (7:3 hexane/
ethyl acetate), 45 mg (78%) of the cyclized diacetate. This
Acid ic Tr ea tm en t for Ep im er iza tion . By the usual
treatment with glacial acetic acid (5 mL), a solution of 31 (100
mg, 0.24 mmol; in 24 mL of EtOH) was refluxed for 48 h,
J . Org. Chem, Vol. 68, No. 3, 2003 863

Madrigal et al.
yielding 31 (60 mg, 60%) and 42 (40 mg, 36%) after flash
chromatography (2:3 hexane/ethyl acetate).
1583. 1H NMR (CDCl3): 2.61 (s, 3H); 3.85 (s, 6H); 3.99 (s, 3H);
5.36 (s, 2H); 6.61 (s, 2H); 7.70 (m, 2H); 7.92 (m, 2H); 9.24 (m,
2H). 13C NMR (CDCl3): 21.5; 56.2, 61.1; 66.7; 107.7 (2C); 125.1;
126.9; 127.3; 127.7; 128.0; 128.4 (2C); 128.5, 129.0; 130.0;
133.7; 134.8; 135.4; 138.0; 139.4; 141.7; 153.0 (2C); 167.9;
169.0. MS (FAB) (m/z): 459 (M+ + 1, 5). Anal. Calcd for
(()-Eth yl (7R,8S,9S)-9-Hyd r oxym eth yl-10-oxo-7-(3,4,5-
t r im et h oxyp h en yl)-7,8,9,10-t et r a h yd r ocycloh ep t a [d ,e]-
n a p h th a len e-8-ca r boxyla te (42). IR (CHCl3): 3417; 1778;
1688. 1H NMR (CDCl3): 1.31 (t, 3H, J 1 ) 6.4); 3.50 (s, 6H);
3.40 (dd, 1H, J 1 ) 3.0, J 2 ) 7.8); 3.75 (s, 3H); 3.85 (m, 1H);
4.03 (d, 1H, J ) 7.6); 4.24 (dd, 1H, J 1 ) 3.2, J 2 ) 7.6); 4.26 (q,
2H, J 1 ) 6.4); 5.04 (d, 1H, J ) 3.0); 6.08 (s, 2H); 7.45 (dd, 1H,
J 1 ) 1.8, J 2 ) 7.0); 7.46 (t, 1H, J ) 7.0); 7.53 (t, 1H, J ) 7.0);
C
27H22O7: C, 70.73; H, 4.84. Found: C, 7.69; H, 4.70.
Ack n ow led gm en t. We thank Mr. Nicholas Skinner
(Languages Service; Universidad de Salamanca) for the
revision of the English of the manuscript. Financial
support came from J unta de Castilla y Leo´n (SA073/
02), Spanish DGESIC-MCyT (PPQ2001-1977), and E.C.
(Feder Funds and COST contract BIO4CT98-0451).
B.M. thanks the MCyT for her predoctoral grant posi-
tion.
7.61 (dd, 1H, J 1 ) 1.4, J 2 ) 7.0); 7.90 (dd, 1H, J 1 ) 1.8, J 2
)
7.6); 8.00 (dd, 1H, J 1 ) 1.4, J 2 ) 7.6). 13C NMR (CDCl3): 14.4;
48.6; 52.1; 52.5; 55.8 (2C); 60.9; 61.7; 62.0; 105.3 (2C); 125.3;
126.5; 127.2; 128.6; 129.2; 129.8; 131.2; 133.0; 134.5; 135.1;
136.3; 138.7; 153.3 (2C); 173.1; 204.8. MS (FAB) (m/z): 465
(M+ + 1, 5). Anal. Calcd for C28H27O7: C, 69.81; H, 6.08.
Found: C, 69.44; H, 6.01.
Tr ea tm en t w ith Ac2O. Compound 38 (100 mg, 0.24 mmol)
was treated with an excess of acetic anhydride under argon.
The reaction mixture was stirred at reflux for 7 h; the reaction
was quenched with water, and the mixture was then worked-
up. Flash chromatography (8:2 hexane/ethyl acetate) of the
crude product afforded 43 (70 mg, 62%).
Su p p or tin g In for m a tion Ava ila ble: Fully detailed ex-
perimental procedures for the synthesis, as well as character-
ization of the compounds described and several minor products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
8-oxo-7-(3,4,5-Tr im et h oxy-p h en yl)-8,10-d ih yd r o-fu r o-
[3,4-b]p h en a n th r en -11-yl Aceta te (43). IR (CHCl3): 1770;
J O0263364
864 J . Org. Chem., Vol. 68, No. 3, 2003