Acid-catalyzed cyclization of 2,3-dibenzylidenesuccinates: Synthesis of lignans (±)-cagayanin and (±)-galbulin

Article abstract of DOI:10.1021/jo0161025

Acid-catalyzed cyclizations of E,E-dibenzylidenesuccinate esters have been developed as an efficient synthetic route to 1-aryl-1,2-dihydronaphthalenes. This reaction has been used in the synthesis of the naturally occurring lignans (±)-cagayanin and (±)-galbulin.

Full text of DOI:10.1021/jo0161025

8606
J . Org. Chem. 2001, 66, 8606-8611
Acid -Ca ta lyzed Cycliza tion of 2,3-Diben zylid en esu ccin a tes:
Syn th esis of Lign a n s (()-Ca ga ya n in a n d (()-Ga lbu lin
Probal K. Datta, Chi Yau, Timothy S. Hooper, Brigitte L.Yvon, and J ames L. Charlton*
Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2
charltn@cc.umanitoba.ca
Received September 9, 2001
Acid-catalyzed cyclizations of E,E-dibenzylidenesuccinate esters have been developed as an efficient
synthetic route to 1-aryl-1,2-dihydronaphthalenes. This reaction has been used in the synthesis of
the naturally occurring lignans (()-cagayanin and (()-galbulin.
Sch em e 1. Cycliza tion of F u lgid es a n d
F u lgim id es
In tr od u ction
The 1,2-dihydronaphthalene carbon skeleton is found
in many lignans, a class of natural products found in
plants. Although many methods have been devised
to prepare such lignans,1-10 only a few have made use
of E,E-dibenzylidenesuccinate derivatives as starting
materials for such syntheses. Among the exceptions are
the photochemical and thermal cyclizations of fulgides
and fulgimides, the cyclic anhydrides and imides of
E,E-dibenzylidenesuccinic acids11-20 (Scheme 1). Reports
have also been made of the photochemical cyclization
of the corresponding lactones21,22 (Scheme 1).
There appears to be only one example of the photo-
cyclization reaction of an acyclic derivative of an E,E-
dibenzylidenesuccinate22 (Scheme 2).
The ease with which E,E-dibenzylidenesuccinates can
be prepared by the Stobbe condensation makes them
Sch em e 2. Cycliza tion of a n Acyclic
E,E-Diben zylid en esu ccin a te Der iva tive
* Author to whom correspondence should be addressed. Telephone:
(204) 474-9267. Fax: (204) 474-7608.
(1) Ward, R. S. Chem. Soc. Rev. 1982, 11, 75.
(2) Whiting, D. A. Nat. Prod. Rep. 1985, 2, 191.
(3) Whiting, D. A. Nat. Prod. Rep. 1987, 4, 499.
(4) Whiting, D. A. Nat. Prod. Rep. 1990, 7, 349.
(5) Ward, R. S. Tetrahedron 1990, 15, 5029.
(6) Ward, R. S. Nat. Prod. Rep. 1993, 10, 1.
(7) Ward, R. S. Nat. Prod. Rep. 1995, 12, 183.
(8) Ward, R. S. Nat. Prod. Rep. 1997, 14, 43.
(9) Cow, C.; Leung, C.; Charlton, J . L. Can. J . Chem. 2000, 78, 553.
(10) Yvon, B. L.; Datta, P. K.; Le, T. N.; Charlton, J . L. Synthesis
2001, 1556.
(11) Boeyens, J . C. A.; Denner, L.; Perold, G. W. J . Chem. Soc.,
Perkin Trans. 2 1988, 1749.
(12) Crescente, O.; Heller, H. G.; Oliver, S. J . Chem. Soc., Perkin
Trans. 1 1979, 150.
(13) Heller, H. G.; Oliver, S.; Shawe, M. J . Chem. Soc., Perkin Trans.
1 1979, 154.
(14) Anjaneyulu, A. S. R.; Raghu, P.; Ramakrishna, R. Indian J .
Chem. B 1979, 18, 535.
(15) Hart, R. J .; Heller, H. G.; Megit, R. M.; Szewczyk, M. J . Chem.
Soc., Perkin Trans. 1 1975, 2227.
attractive starting materials for lignan synthesis, and so,
we embarked on a program to explore more general
methods of achieving the cyclization of E,E-dibenzyli-
denesuccinates to dihydronaphthalenes.
Because simple diesters of E,E-dibenzylidenesuccinate
are very easily prepared, we began our investigation with
a study of these esters. J udging from previous observa-
tions for the photochemical cyclization shown in Scheme
2, it was expected that the photocyclization of E,E-
dibenzylidenesuccinate diesters would give conrotatory
ring closure. A subsequent suprafacial 1,5-sigmatropic
shift of hydrogen (in accordance with the pericyclic
reaction rules) would afford dihydronaphthalenes with
a cis relationship between the substituents on positions
1 and 2 (as in Scheme 2). On the other hand, an acid-
(16) Heller, H. G.; Szewczyk, M. J . Chem. Soc., Perkin Trans. 1 1974,
1487.
(17) Heller, H. G.; Megit, R. M. J . Chem. Soc., Perkin Trans. 1 1974,
923.
(18) Hart, R. J .; Heller, H. G. J . Chem. Soc., Perkin Trans. 1 1972,
1321.
(19) Hart, R. J .; Heller, H. G.; Salisbury, K. J . Chem. Soc., Chem.
Commun. 1968, 1627.
(20) Ayres, D. C.; Carpenter, B. G.; Denney, R. C. J . Chem. Soc.
1965, 3578.
(21) Momose, T.; Kanai, K.-I.; Nakamura, T.; Kuni, Y. Chem. Pharm.
Bull. 1977, 25, 2755.
(22) Dyachenko, O. A.; Atovmyan, L. O.; Aldoshin, S. M.; Polyakov,
A. E.; Kostyanovskii, R. G. J . Chem. Soc., Chem. Commun. 1976, 50.
10.1021/jo0161025 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/14/2001

Acid-Catalyzed Cyclization of 2,3-Dibenzylidenesuccinates
J . Org. Chem., Vol. 66, No. 25, 2001 8607
Sch em e 3. Syn th esis of Dieth yl
E,E-Diben zylid en esu ccin a tesa
F igu r e 1. Cagayanin and galbulin.
catalyzed cyclization would likely provide dihydronaph-
thalenes with the thermodynamically more stable trans
relationship between these two substituents.
Both of these predictions have been realized, and the
methodolgy has been exploited to prepare the naturally
occurring lignans (()-cagayanin, and (()-galbulin (Figure
1).
Cagayanin (1) was first isolated from the nutmeg of
Myristica cagayanesis Merr, and the extract has been
used medicinally in China.23 Until now, no synthetic
approach has been reported for this compound. Galbulin
(2) was first isolated from Himantandra baccata Bail in
1954.24 A number of papers25-35 have reported the
synthesis of galbulin (2), many starting from other known
lignans of similar structure. Most recently, R. J . Whitby
et al. described an interesting stereoselective synthesis
of (()-galbulin using a metal-mediated cyclization of a
1,7 diene.35
a
(i) Ar1-CHO, KOt-Bu, t-BuOH; (ii) EtI, K2CO3, acetone; (iii)
2 Ar1-CHO, NaH, DMF; (iv) Ar2-CHO, NaOEt, EtOH; (v) EtI,
K2CO3, acetone/DMSO.
Sch em e 4. P h otocycliza tion of a n
E,E-Diben zylid en esu ccin a te Diester
Resu lts a n d Discu ssion
Symmetrical 2,3-dibenzylidenesuccinate diethyl esters
were prepared by a one-pot, double Stobbe condensation
reaction of diethyl succinate with 2 equiv of an aromatic
aldehyde followed by esterification with ethyl iodide in
acetone/DMSO (Scheme 3). Unsymmetrical 2,3-dibenzyli-
denesuccinate diethyl esters were prepared by a two-step
Stobbe condensation reaction using two different alde-
hydes (Scheme 3).
We began our investigation of the cyclization of the
E,E-dibenzylidenesuccinate diesters by studying the
photochemistry of diethyl E,E-bis-(3,4,5-trimethoxyben-
zylidene)succinate (4a a ). Irradiation of 4a a in ethanol
with 0.01 M TFA for 2 h followed by chromatographic
separation, yielded the cis- (34%) and trans- (2%) 1,2-
dihydronaphthylene diethyl esters 5a p and 6a p , respec-
tively (Scheme 4). An acidic solvent was used, as it was
found that this suppressed the formation of some minor
side products.
This result encouraged us to study the photochemistry
of other dibenzylidenesuccinate diethyl esters, such as
E,E-bis-(2,4,5-trimethoxybenzylidene)succinate diethyl
ester 4d d . Irradiation of 4d d under the same conditions
as used for 4a a gave only recovery of starting material.
Employing longer irradiation times, changing the solvent
to ethyl acetate, and using a basic or neutral solvent
(K2CO3 in ethanol or pure ethanol) failed to produce
any significant amounts of cyclized product. In some
instances, the starting material was slowly consumed
to produce a complex mixture of products. The NMR
spectrum of the crude product mixture from these latter
reactions exhibited peaks that could be interpreted
to indicate E,Z-isomerization of the starting material
(although these isomers were not isolated or character-
ized). Irradiation of diesters 4bb and 4cc also did not
produce significant amounts of the cyclized products. As
a result of these unpromising results, we began an
investigation of the acid-catalyzed cyclization of the
E,E-dibenzylidenesuccinate diethyl esters.
(23) (a) Kuo, Y.-H.; Wu, R.-E. J . Chin. Chem. Soc. 1985, 32, 177.
(b) Kuo, Y.-H.; Lin, S.-T.; Wu, R.-E. Chem. Pharm. Bull. 1989, 37, 2310.
(24) Hughes, G. K.; Ritchie, E. Aust. J . Chem. 1954, 7, 104.
(25) Muller, A.; Vajda, M. J . Org. Chem. 1952, 17, 800.
(26) Carnmalm, B. Acta Chem. Scand. 1954, 8, 1827.
(27) Schrecker, A. W.; Hartwell, J . L. J . Am. Chem. Soc. 1955, 77,
432.
(28) Birch, A. J .; Milligan, B.; Smith, E.; Speake, R. N. J . Chem.
Soc. 1958, 4471.
(29) Crossley, N. S.; Djerassi, C. J . Chem. Soc. 1962, 1459.
(30) Perry, C. W.; Kalnins, M. V.; Deitcher, K. H. J . Org. Chem.
1972, 37, 4371.
(31) Biftu, T.; Hazra, B. G.; Stevenson, R.; Williams, J . R. J . Chem.
Soc., Perkin Trans. 1 1978, 1147.
(32) Liu, J .-S.; Huang, M.-F.; Gao, Y.-L.; Findlay, J . A. Can. J . Chem.
1981, 59, 1680.
(33) Landais, Y.; Lebrun, A.; Lenain, V.; Robin, J .-P. Tetrahedron
Lett. 1987, 28, 5161.
(34) Buckleton, J . S.; Cambie, R. C.; Clark, G. R.; Craw, P. A.;
Rickard, C. E. F.; Rutledge, P. S.; Woodgate, P. D. Aust. J . Chem. 1988,
41, 305.
After some experimentation, it was discovered that
diethyl ester 4a a would undergo cyclization in the
presence of trifluoromethanesulfonic acid (triflic acid) to
give the expected trans-1,2-dihydronaphthalene 6a p ,
along with some dearylyzed product 7p . The generality
(35) Kasatkin, A. N.; Checksfield, G.; Whitby, R. J . J . Org. Chem.
2000, 65, 3236.

8608 J . Org. Chem., Vol. 66, No. 25, 2001
Datta et al.
Sch em e 6. Mech a n ism of Acid -Ca ta lyzed
Sch em e 5. Acid -Ca ta lyzed Cycliza tion of Dieth yl
E,E-Diben zylid en esu ccin a tes
Dea r yla tion
Sch em e 7. Mech a n ism of Acid -Ca ta lyzed
Cycliza tion
Ta ble 1. Acid -Ca ta lyzed Cycliza tion of
2,3-Diben zylid en esu ccin a te Dieth yl Ester s.
acid
(equiv)
time
(h)
products
entry
diester
(yields, %)a
1
2
3
4
5
6
7
8
9
4a a
4bb
4cc
4d d
4ee
4ff
4gg
4gg
4bc
4a c
4a e
4cf
1.5
1.5
1.0
1.5
0.1
0.1
0.1
1.5
1.5
1.0
0.1
0.1
8
18
3
22
4
22
120
17
3
18
46
21
6a p (63), 7p (17)b
6bq (36), 7q (∼5)b,c
6cr (59), 7r (17)
6d s (55)
6cb prepared by an alternate route.7 Similarly, diester
4a c gave the two regeoisomers 6a r (24%) and 6cp (16%),
along with dearylized product 7p (43%). Unsymmetrical
3,4-dibenzyledenesuccinate diesters, in which one of the
aromatic rings bears a 3′-methoxy group (4a e and 4cf),
appear to selectively cyclize on the other aryl ring (the
ring without the 3′-methoxy substituent), but in these
cases, no dihydronaphthalenes were isolated, as they
were quantitatively converted to the dearylized products
(97 and 95%, respectively) under the reaction conditions.
The driving force for the dearylization most likely arises
from the aromatization of the dihydronaphthalene to the
more stable naphthalene derivatives.
6et (97)
6fu (38)c
6gv (∼10)d
6gv (85)
6br + 6cq (68), 7q (11)
6a r (24), 6cp (16), 7p (43)c
7p (97)
10
11
12
7r (95)
Isolated yields. Starting material (25%) was recovered. c Re-
a
b
d
action was carried out at room temperature. Yield was estimated
from 1H NMR spectrum of the crude reaction mixture.
Dearylation most likely involves acid-catalyzed elimi-
nation of the aryl group from the dihydronaphthalene
products by a two-step mechanism with protonation of
the ipso carbon as the first step. Similar dearylation
mechanisms have been proposed previously.36 A possible
mechanism is shown in Scheme 6.
J udging from the effects of substituents on the ease of
cyclization, as well as previous mechanistic investigations
of the cyclization of aryl butyl systems,37 it seems likely
that the catalyzed cyclization of dibenzylidenesuccinates
follows, at least in part, path B, as shown in Scheme 7.
of the reaction was demonstrated by application to a
variety of dibenzylidenesuccinate diethyl esters (Scheme
5).
The results are summarized in Table 1.
The results from Table 1 show that the reactivity of
the diesters highly depends on the position of the alkoxy
substituents on the aryl rings. For instance, cyclization
of diesters 4a a and 4bb was sluggish and did not go to
completion. Prolonged heating or the use of excess triflic
acid decreased the yields of the desired products while
making the dearylized compounds (7p and 7r ) the major
products. Moderate yields were obtained using 1.5 equiv
of triflic acid. Diester 4cc cyclized more readily and gave
6cr in 59% yield. 4ee and 4ff, bearing 3′-methoxy groups,
cyclized rapidly in the presence of catalytic amounts (10
mol %) of triflic acid. Diester 4gg required 1.5 equiv of
triflic acid and 17 h to yield 85% of 6gv. Unsymmetrical
dibenzyledenesuccinate diester 4bc gave 68% of an
inseparable mixture (3:1 ratio) of what appeared to be
two regeoisomers, along with 11% of dearylized product
(7q). The major ring cyclization appears to have occurred
on the 3,4-dimethoxyphenyl ring, as determined by a
comparison of the NMR spectrum of the mixture of
cyclized products to the spectrum of dihydronaphthalene
Syn th eses of (()-Ca ga ya n in (1) a n d
(()-Ga lbu lin (2)
Syntheses of (()-cagayanin and (()-galbulin were
completed following the procedure shown in Scheme 8.
The dihydronaphthalenes diesters 6bq and 6cr were
prepared using the method described above in 36 and
59% yields, respectively (Table 1). Palladium-catalyzed
hydrogenation of the 1,2-dihydronaphthalenes 6bq and
(36) Ruehl, K. E.; Matyjaszewski, K. J . Organomet. Chem. 1991,
410, 1.
(37) Winstein, S.; Heck, R. F. J . Org. Chem. 1972, 37, 825.

Acid-Catalyzed Cyclization of 2,3-Dibenzylidenesuccinates
J . Org. Chem., Vol. 66, No. 25, 2001 8609
1
These compounds had H NMR, 13C NMR, and mass spectral
Sch em e 8. Syn th esis of Ca ga ya n in a n d Ga lbu lin a
properties identical to those previously reported.9,10
Gen er a l P r oced u r e B for th e P r ep a r a tion of Un sym -
m etr ica l Dieth yl E,E-Diben zylid en esu ccin a tes. Sodium
ethoxide (3.0 mmol) was prepared by dissolving sodium (0.069
g, 3.0 mmol) in absolute ethanol (5 mL) in a 100-mL three-
neck round-bottom flask. A mixture of diester 3a or 3c (2.0
mmol) and an appropriate aldehyde (2.5 mmol) in absolute
ethanol (20 mL) was slowly added (ca. 15 min) through a
dropping funnel. The solution was then refluxed under nitro-
gen atmosphere for 3-5 h. The mixture was cooled to room
temperature and evaporated under reduced pressure, distilled
water (50 mL) was dded, and the mixture was extracted with
ethyl acetate. The organic layers were discarded, and the
aqueous layer was acidified with 10% aqueous HCl (pH 1)
and extracted with EtOAc. The combined organic fractions
were washed with brine, dried over magnesium sulfate, and
concentrated in vacuo to give the crude product. This crude
product was dissolved in acetone/DMSO (4:1, 25 mL), solid
K2CO3 (1.39 g, 10.0 mmol) and ethyl iodide (0.78 mL, 10 mmol)
were added, and the mixture was refluxed under nitrogen for
6-15 h. The reaction mixture was cooled to room temperature,
the acetone was evaporated, distilled water (60 mL) was added,
and the mixture was extracted with EtOAc. The combined
organic extracts were washed with brine, dried with magne-
sium sulfate, and concentrated to give the desired 2,3-
dibenzylidenesuccinate diethyl esters in 81-97% isolated
yields (symmetrical diesters 4a a and 4cc were also prepared
using this procedure).
Dieth yl E,E-Bis-(3,4,5-tr im eth oxyben zylid en e)su cci-
n a te (4a a ). 4a a was prepared from 3a and 3,4,5-trimethoxy-
benzaldehyde using general procedure B. The crude product
was purified by column chromatography using 35-45% EtOAc
in hexanes to give a light yellow oil, which solidified on
standing (87% from 3a ), mp 144.0-145.0 °C (from hexanes/
EtOAc). 1H NMR (CDCl3) δ 1.08 (t, 6H, J ) 7.1 Hz), 3.74
(s, 12H), 3.80 (s, 6H), 4.14 (m, 4H), 6.75 (s, 4H), 7.80 (s, 2H);
13C NMR (CDCl3) δ 14.1 (2C), 56.0 (4C), 60.9 (2C), 61.1 (2C),
107.1 (4C), 126.8 (2C), 130.2 (2C), 139.4 (2C), 142.1 (2C), 153.0
(4C), 166.8 (2C); mass spectrum m/z (relative intensity) 530
(M+, 6), 317 (17), 289 (13), 181 (100); HRMS calcd for C28H34O10
530.2151, found 530.2146.
a
(i) H2, Pd, EtOH; (ii) LAH, THF, rt; (iii) Tf2O, CH2Cl2, Et3N,
-10 °C; (iv) LAH, THF, -10 °C.
6cr gave aryltetralin derivatives 8bq and 8cr in 64 and
92% yields, respectively. Reduction of 8bq and 8cr with
lithium aluminum hydride in THF gave the diols 9bq
and 9cr , respectively, in nearly quantitative yields. These
products were immediately used for the next reaction
without purification. The crude diols were converted to
their corresponding ditriflates using triflic anhydride in
CH2Cl2 at -10 °C and then reduced using lithium
aluminum hydride in THF. This provided the natural
products (()-cagayanin (1) (77%) and (()-galbulin (2)
(43%). Syntheses of (()-cagayanin and (()-galbulin were
completed in overall 18% (from 3bb) and 23% (from 3cc)
yields, respectively. The present method should be ap-
plicable to the syntheses of other lignans and related
compounds.
Exp er im en ta l Section
1H and 13C NMR spectra were recorded on a Bruker AM-
300 FT instrument using residual CHCl3 in CDCl3 as the
internal standard unless otherwise specified. Silicycle silica
gel was used for all chromatography. HRMS/mass spectra were
obtained on a VG Analytical 7070E-HF instrument.
Gen er a l P r oced u r e A for th e P r ep a r a tion of Sym -
m etr ical Dieth yl 2,3-Diben zyliden esu ccin ates (4bb, 4dd-
4gg). A three-neck round-bottom flask (100 mL) fitted with
reflux condenser and dropping funnel was charged with 1.260
g of NaH (52.5 mmol, 57% in mineral oil) and dry DMF (10
mL). A mixture of aldehyde (25 mmol) and diethylsuccinate
(10 mmol) in 50 mL of dry DMF was slowly added to the stirred
suspension via the dropping funnel. After addition was com-
plete, the mixture was heated to reflux (100 °C bath temper-
ature) and stirred under a nitrogen atmosphere overnight. The
mixture was cooled to room temperature, aqueous KOH
solution (0.1 M, 30 mL) was added, the solution was refluxed
for 1.5 h. The solution was then cooled to room temperature,
water (60 mL) was added, and the solution was extracted with
EtOAc, with these extracts being discarded. The aqueous layer
was acidified with 10% HCl (pH 1) and extracted again with
EtOAc. The combined EtOAc extracts were washed with water
and brine, dried over magnesium sulfate, and evaporated to
give the crude product. The crude product was dissolved in
acetone/DMSO (3:1, 50 mL), ethyl iodide (7.28 mL, 93 mmol)
and solid K2CO3 (12.9 g, 93 mmol) were added, and the mixture
was refluxed under nitrogen atmosphere overnight. The reac-
tion mixture was cooled to room temperature and concentrated
under reduced pressure, water (100 mL) was added, and the
mixture was extracted with EtOAc. The combined organic
extracts were washed with water and brine, dried over
magnesium sulfate, and evaporated. Column chromatography
(ethyl acetate/hexanes) yielded the pure products in 50-60%
yield (based on diethyl succinate).
P h otor ea ction of Dieth yl E,E-Bis-(3,4,5-tr im eth oxy-
ben zylid en e)su ccin a te (4a a ). A solution of the diethyl ester
4a a (0.202 g, 0.381 mmol) in a 0.01 M solution of TFA in
anhydrous ethanol (60 mL) in a Pyrex test tube was purged
vigorously with N2 for 5 min (the nitrogen atmosphere was
maintained for the duration of the reaction), the test tube was
sealed, and the mixture was irradiated for 3 h using a medium-
pressure Hanovia mercury lamp. The solution was evaporated,
and the residue was redissolved in CH2Cl2, dried over anhy-
drous magnesium sulfate, and concentrated under vacuum to
afford a pale yellow oil (0.213 g). The product mixture was
purified by flash column chromatography on silica gel (100 mL)
using 30% EtOAc in hexanes to afford two fractions. The first
chromatography fraction (0.004 g, 2%) exhibited a 1H NMR
spectrum identical to that of the trans-dihydronaphthalene
6a p .9
The second eluted fraction (0.070 g, 34%) was a colorless
wax: 1H NMR (CDCl3) δ 0.89 (t, 3H, J ) 7.2 Hz), 1.24 (t, 3H,
J ) 7.2 Hz), 3.46 (s, 3H), 3.71 (s, 3H), 3.72 (s, 6H), 3.82 (s,
3H), 3.86 (s, 3H), 4.08 (dd, 1H, J ) 2.8, 9.1 Hz), 4.17 (m, 2H),
4.76 (d, 1H, J ) 9.1 Hz), 6.32 (s, 2H), 6.63 (s, 1H), 7.36 (d, 1H,
J ) 2.8 Hz); 13C NMR (CDCl3) δ 13.8, 14.3, 40.5, 48.1, 56.10,
56.13 (2C), 60.4, 60.5, 60.7, 60.8 (2C), 106.4 (2C), 108.0, 123.7,
126.2, 127.1, 135.4, 136.4, 137.2, 144.2, 151.1, 152.6 (2C),
152.9, 167.3, 171.5; mass spectrum m/z (relative intensity) 530
(M+, 100), 484 (44), 456 (62), 411 (65), 384 (33), 358 (69); HRMS
calcd for C28H34O10 530.2151, found 530.2139.
Gen er a l P r oced u r e for Acid -Ca ta lyzed Cycliza tion of
Dieth yl E,E-3,4-Diben zyliden esu ccin ates. A two-neck round-
bottom flask fitted with a condenser was purged with nitrogen.
A solution of diester (0.5 mmol) in freshly distilled CH2Cl2 (10
mL) was added to the reaction flask via cannula. The solution
was warmed to 45 °C, triflic acid was added (see Table 1), and
Syn th esis of Dieth yl E-(3,4,5-Tr im eth oxyben zylid en e)-
su ccin a te (3a ) a n d E-(3,4-Dim eth oxyben zylid en e)su cci-
n a te (3c). Diethyl esters 3a and 3c were prepared according
to a literature procedure9,10 in 67 and 85% yields, respectively.

8610 J . Org. Chem., Vol. 66, No. 25, 2001
Datta et al.
the solution was refluxed under nitrogen atmosphere for
several hours (see Table 1). The reaction mixture was cooled
to room temperature, quenched with 5% aqueous sodium
bicarbonate solution (10 mL), and extracted with CH2Cl2. The
combined organic extracts were washed with brine, dried with
magnesium sulfate, and concentrated in vacuo. The crude
product was purified by silica gel column chromatography
using EtOAc in hexanes to produce pure 1,2-dihydronaphtha-
lene derivatives.
J ) 10.8 Hz), 3.06 (m, 2H), 3.13 (m, 1H), 3.96 (m, 2H), 4.08
(m, 1H, J ) 11.0 Hz), 4.14 (m, 2H), 5.85 (m (AB), 2H), 5.92 (s,
2H), 6.22 (s, 1H), 6.54 (d, 1H, J ) 1.6 Hz), 6.56 (s, 1H), 6.60
(dd, 1H, J ) 1.7, 7.8 Hz), 6.71 (d, 1H, J ) 7.8 Hz); 13C NMR
(CDCl3) δ 13.9, 14.1, 32.4, 43.4, 49.2, 51.5, 60.4, 60.9, 100.8,
100.9, 107.7, 107.9, 109.0, 109.1, 122.6, 127.2, 131.0, 136.8,
146.2, 146.3, 146.6, 147.9, 173.5, 173.9; mass spectrum m/z
(relative intensity) 440 (M+, 32), 366 (47), 263 (26), 235 (21),
220 (12), 135 (22); HRMS calcd for C24H24O8 440.1471 found
440.1473.
The 1H NMR, 13C NMR, and mass spectral properties of
trans-1,2-dihydro-naphthalene-2,3-dicarboxylate derivatives
6a p , 6bq, 6cr , 6et, 6br , 6cr , 6a r , and 6cp were identical to
those previously reported.9,10
Diet h yl
r -1-(3,4-Dim et h oxyp h en yl)-6,7-d im et h oxy-
1,2,3,4-tetr ah ydr on aph th alen e-t-2,c-3-dicar boxylate (8cr ).
Dihydronaphthalene diester (6cr ) (0.15 g, 0.3 mmol) was
stirred with Pd/C (0.023 g, 0.2 mmol) under hydrogen atmo-
sphere for 18 h, as described above, to afford a colorless oil
(0.14 g, 92%). The product was used in the next step without
further purification. 1H NMR (CDCl3) δ 0.96 (t, 3H, J ) 7.1
Hz), 1.24 (t, 3H, J ) 7.1 Hz), 3.00 (t, J ) 10.8 Hz), 3.06-3.24
(m, 3H), 3.57 (s, 3H), 3.79 (s, 3H), 3.84 (s, 3H), 3.86 (s, 3H),
3.92 (m, 2H), 4.12 (m, 2H), 4.14 (d, 1H of C1, J ) 10.7 Hz),
6.22 (s, 1H), 6.59 (d, 2H, J ) 2.2 Hz), 6.68 (dd, 1H, J ) 2.1,
8.2 Hz), 6.78 (d, 1H, J ) 8.2 Hz); 13C NMR (CDCl3) δ 13.9,
14.1, 31.9, 43.4, 49.0, 51.5, 55.8, 55.9, 60.3, 60.9, 110.7, 110.9,
111.9, 112.1, 121.7, 126.2, 129.9, 135.4, 147.5, 147.7, 148.0,
149.0, 173.7, 174.1; mass spectrum m/z (relative intensity) 472
(M+, 50), 398 (42), 325 (100), 269 (22), 236 (20), 151 (29); HRMS
calcd for C26H32O8 472.2097 found 472.2086.
Dieth yl 7-Meth oxy-r -1-(4-m eth oxyp h en yl)-tr a n s-1,2-d i-
h yd r on a p h th a len e-t-2,3-d ica r boxyla te (6d s). The crude
product was purified by column chromatography using 15-
20% EtOAc in hexanes to give a light yellow oil. 1H NMR
(CDCl3) δ 1.13 (t, 3H, J ) 7.1 Hz), 1.29 (t, 3H, J ) 7.1 Hz),
3.74 (s, 3H), 3.76 (s, 3H), 3.98 (d, 1H, J ) 3.4 Hz), 4.07 (m,
2H,), 4.21 (m, 2H), 4.61 (d, 1H, J ) 3.4 Hz), 6.64 (d, 1H, J )
2.5 Hz), 6.75 (d, 2H, J ) 8.7 Hz), 6.79 (dd, 1H, J ) 2.5, 8.3
Hz), 6.97 (d, 2H, J ) 8.7 Hz), 7.28 (d, 1H, J ) 8.4 Hz), 7.67 (s,
1H); 13C NMR (CDCl3) δ 14.0, 14.2, 46.0, 47.3, 55.17, 55.24,
60.6. 61.0, 112.8, 113.9 (2C), 114.8, 122.8, 124.7, 128.7 (2C),
130.6, 134.4, 137.1, 139.3, 158.4, 161.4, 166.7, 172.5; mass
spectrum m/z (relative intensity) 410 (M+, 9), 336 (100), 308
(10), 291 (49), 264 (63), 250 (14), 227 (19), 189 (11), 149 (19),
135 (26), 121 (22); HRMS calcd for 410.1729 C24H26O6 found
410.1741.
Diet h yl 6,7,8-Tr im et h oxyn a p h t h a len e-2,3-d ica r b ox-
yla te (7p ). The crude product was purified by column chro-
matography using 30% EtOAc in hexanes to give a colorless
oil, which solidified on standing, mp 50.0-52.0 °C (from
hexanes/ether). 1H NMR (CDCl3) δ 1.39 (t, 3H, J ) 7.1 Hz),
1.39 (t, 3H, J ) 7.1 Hz), 3.98 (s, 6H), 4.06 (s, 3H), 4.38 (q, 2H,
J ) 7.1 Hz), 4.40 (q, 2H, J ) 7.1 Hz), 6.99 (s, 1H), 8.04 (s, 1H),
8.44 (s, 1H); 13C NMR (CDCl3) δ 14.1, 14.2, 56.0 (CH3), 61.2,
61.4, 61.5, 61.6, 102.8, 124.2, 124.5, 126.6, 128.2, 129.0, 131.0,
142.5, 148,4, 155.2, 167.9, 168.0; mass spectrum m/z (relative
intensity) 362 (M+, 100), 347 (32), 319 (16), 289 (37), 245 (9),
231 (12), 202 (9); HRMS calcd for C19H22O7 362.1365 found
362.1347.
Dieth yl 6,7-Meth ylen ed ioxyn a p h th a len e-2,3-d ica r box-
yla te (7q). The crude product was purified by column chro-
matography using 35% EtOAc in hexanes to give a colorless
viscous oil, which solidified on standing at 4 °C, mp 107.0-
109.0 °C (from hexanes/ether). 1H NMR (CDCl3) δ 1.39 (t, 6H,
J ) 7.1 Hz), 4.39 (q, 4H, J ) 7.1 Hz), 6.01(s, 2H), 7.15 (s, 2H),
8.02 (s, 2H);13C NMR (CDCl3) δ 14.2 (2C), 61.5 (2C), 101.7,
104.4 (2C), 127.6 (2C), 128.7 (2C), 131.0 (2C), 149.7 (2C), 167.9
(2C); mass spectrum m/z (relative intensity) 316 (M+, 42), 271
(6), 243 (100), 149 (31); HRMS calcd for C17H16O6 316.0946
found 316.0934.
Dieth yl 6,7-Dim eth oxyn a p h th a len e-2,3-d ica r boxyla te
(7r ). The crude product was purified by column chromatog-
raphy using 30% EtOAc in hexanes to give a colorless viscous
oil, which solidified on standing at 4 °C, mp 123.0-125.0 °C
(from hexanes/EtOAc). 1H NMR (CDCl3) δ 1.38 (t, 6H, J ) 7.1
Hz), 3.99 (s, 6H), 4.39 (q, 4H, J ) 7.1 Hz), 7.15 (s, 2H), 8.07 (s,
2H);13C NMR (CDCl3) δ 14.2 (2C), 56.0 (2C), 61.5 (2C), 106.7
(2C), 127.3 (2C), 128.2 (2C), 129.5 (2C), 151.4 (2C), 168.0 (2C);
mass spectrum m/z (relative intensity) 332 (M+, 43), 287 (17),
259 (100), 214 (17), 186 (22), 115 (9); HRMS calcd for C18H20O6
332.1259 found 332.1261.
r -1-(3,4-Met h ylen ed ioxyp h en yl)-6,7-m et h ylen ed ioxy-
1,2,3,4-t et r a h yd r on a p h t h a len e-t-2,c-3-d i(h yd r oxym et h -
yl) (9bq). Aryltetralin diester 8bq (0.020 g, 0.05 mmol) was
dissolved in THF (3 mL) and added to a slurry of lithium
aluminum hydride (LAH) (0.024 g, 0.6 mmol) and dry THF (2
mL) at room temperature. The reaction was stirred under N2
for 0.5 h at room temperature and then worked up using
Fieser’s method.38 In succession, 0.06 mL of water, 0.06 mL of
15% aqueous NaOH, and 0.18 mL of water were added to
quench the reaction. The solution was diluted with EtOAc (15
mL), dried with MgSO4, filtered through Celite, and evapo-
1
rated to give an oil (0.016 g, 100%). H NMR (CDCl3) δ 1.71-
1.83 (m, 1H), 1.93-2.03 (m, 1H), 2.55 (br s, 2H) 2.68 (m, 2H),
3.48 (dd, 1H, J ) 5.2, 11.3 Hz), 3.72 (m, 2H), 3.78 (m, 2H),
5.83 (m (AB), 2H), 5.92 (s, 2H), 6.20 (s, 1H), 6.54 (d, 1H, J )
1.8 Hz), 6.55 (s, 1H), 6.64 (dd, 1H, J ) 1.7, 7.8 Hz), 6.74 (d,
1H, J ) 7.8 Hz); 13C NMR (CDCl3) δ 33.6, 39.8, 48.2, 48.3,
62.7, 66.3, 100.6, 100.9, 107.8, 108.0, 109.1, 109.6, 122.8, 129.2,
132.8, 139.1, 145.7, 145.8, 146.2, 148.0; mass spectrum m/z
(relative intensity) 356 (M+, 100), 338 (32), 307 (73), 280 (54),
267 (50), 238 (52), 210 (27), 185 (26), 173 (50), 152 (41), 135
(89), 115 (29), 76 (19); HRMS calcd for C20H20O6 356.1259
found 356.1262.
r -1-(3,4-Dim eth oxyp h en yl)-6,7-d im eth oxy-1,2,3,4-tetr a -
h yd r on a p h th a len e-t-2,c-3-d i(h yd r oxym eth yl) (9cr ). Aryl-
tetralin diester 8cr (0.14 g, 0.3 mmol) was reduced with LAH
(0.066 g, 1.7 mmol) in THF as described above to yield a
colorless amorphous solid (0.10 g, 92%). This compound had
1H NMR, 13C NMR, and mass spectral properties identical to
those reported previously.39
(()-Ca ga ya n in (1). Aryltetralin diol 9bq (0.016 g, 0.05
mmol) was taken up in dry CH2Cl2 (4 mL), and diisopropyl-
ethylamine (0.018 g, 0.1 mmol) added. The flask was purged
with N2 and cooled to -10 °C in a salt/ice water bath. Triflic
anhydride (0.039 g, 0.1 mmol) in CH2Cl2 (0.5 mL) was added
dropwise to the cooled reaction mixture. The reaction mixture
was stirred under N2 for 1.5 h, and water (3 mL) was added
to quench the reaction. The solution was diluted with CH2Cl2
(5 mL) and washed with saturated aqueous NaHCO3 (2 × 10
mL). The organic fraction was dried with MgSO4, filtered, and
evaporated. The crude product was dissolved in THF (2 mL)
and added to a slurry of LAH (0.018 g, 0.5 mmol) in THF (2
mL) at -10 °C. The reaction mixture was stirred under N2 at
room temperature for 45 min and worked up by Fieser’s
Diet h yl r -1-(3,4-Met h ylen ed ioxyp h en yl)-6,7-m et h yl-
en ed ioxy-1,2,3,4-t et r a h yd r on a p h t h a len e-t-2,c-3-d ica r -
boxyla te (8bq). Dihydronaphthalene diester (6bq) (0.032 g,
0.07 mmol) was dissolved in anhydrous EtOH (15 mL), and
Pd/C (0.015 g, 0.1 mmol) was added. The reaction flask was
flushed and evacuated with H2 several times; then the mixture
was stirred at room temperature for 27 h under H2. The
reaction mixture was filtered through Celite and concentrated
to give a light yellow oil (0.020 g, 64%). The product was used
in the next step with no further purification. 1H NMR (CDCl3)
δ 1.01 (t, 3H, J ) 7.1 Hz), 1.25 (t, 3H, J ) 7.1 Hz), 2.97 (t, 1H,
(38) Fieser, L. F.; Fieser, M. In Reagents for Organic Synthesis; J ohn
Wiley and Sons: New York, 1967; Vol. I, p 584.
(39) Charlton, J . L.; Alauddin, M. M. J . Org. Chem. 1986, 18, 3490.

Acid-Catalyzed Cyclization of 2,3-Dibenzylidenesuccinates
J . Org. Chem., Vol. 66, No. 25, 2001 8611
method (60 µL of water, 60 µL of 15% aqueous NaOH, 180 µL
of water), followed by the addition of EtOAc (20 mL). The
solution was dried with MgSO4, filtered through Celite, and
evaporated to give a colorless oil. This crude product was
purified by column chromatography using 20% EtOAc/hexanes
to give a clear, colorless oil (0.011 g, 77%). This compound had
1H NMR, 13C NMR, and mass spectral properties identical to
those previously reported.23
Ack n ow led gm en t. We are grateful to the Natural
Sciences and Engineering Research Council of Canada
and the University of Manitoba for financial support of
this project.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for 4bb, 4cc, 4d d , 4ff, 4bc, 4a c, 4a e, 4cf, 6fu , and 6gv
1
and 13C and H NMR spectra of 4a a , 4a c, 4a e, 4bb, 4bc, 4cc,
(()-Ga lbu lin (2). Aryltetralin diol 9cr (0.027 g, 0.07 mmol)
was reacted with triflic anhydride and reduced following a
method identical to that described above for 9bq. The crude
product was purified by column chromatography using 30%
EtOAc/hexanes to give a light yellow oil (0.011 g, 43%). This
4cf, 4d d , 4ee, 4ff, 4gg, 5a p , 6d s, 6fu , 6gv, 7p , 7q, 7r , 8bq,
8cr , 9bq, 1, and 2. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
compound had H NMR, 13C NMR, and mass spectral proper-
ties identical to those reported previously.24
J O0161025