Efficient synthesis of 1-aryl-3,4-dihydro-4-hydroxynaphthalene: Application to the stereocontrolled synthesis of (±)-isopicropodophyllin and (±)-isopodophyllotoxin

Full text of DOI:10.1021/jo9609384

9560
J . Org. Chem. 1996, 61, 9560-9563
stereocontrolled hydrogenation of 4 should provide pre-
Efficien t Syn th esis of
cursors of 2 and 3. Additionally, the R,â-unsaturated
ester function of 4 might be suitable for the preparation
of C-1 and/or C-2 functionalized aryltetralin lignans. The
reaction of 4 with oxidizing agents, for example, might
afford the 1,2-epoxy compound. Herein we report an
efficient method for synthesizing 4 and its application
to the synthesis of 2 and 3.
1-Ar yl-3,4-d ih yd r o-4-h yd r oxyn a p h th a len e:
Ap p lica tion to th e Ster eocon tr olled
Syn th esis of (()-Isop icr op od op h yllin a n d
(()-Isop od op h yllotoxin
Tooru Kuroda, Masami Takahashi,
Kazuhiko Kondo,* and Tameo Iwasaki
Pharmaceutical Development Research Laboratory,
Tanabe Seiyaku Co. Ltd., 3-16-89 Kashima,
Yodogawa, Osaka 532, J apan
Resu lts a n d Discu ssion
1-Hydroxy-1,2-dihydronaphthalenes have been shown
to undergo ready dehydration to afford naphthalenes
under acidic conditions.4,5 We expected that we should
be able to avoid the dehydration by careful selection of
acid catalyst and conditions. If this were possible, acid-
promoted isomerization of the adduct 10, generated from
the isobenzofuran 9 and dimethyl maleate, could afford
the dihydronaphthol 4 (Scheme 1). The isobenzofuran 9
in turn would be generated from the acetoxyaldehyde 8
under acidic conditions.6 Thus, a single-step conversion
of 8 into 4 using dimethyl maleate and acid catalysts
could be expected.
Received May 20, 1996
In tr od u ction
The structural complexities and varied biological ac-
tivities of aryltetralin lignans, as exemplified by the
natural product podophyllotoxin (1), make them chal-
lenging synthetic targets.1 Several methods have become
available for the synthesis of podophyllotoxin (1) and its
congeners.2 Rodrigo et al. reported the synthesis of (()-
isopicropodophyllin (2) and (()-isopodophyllotoxin (3)
from piperonal via hydrogenolysis of the Diels-Alder
adduct in 22% and 20% overall yields, respectively.3
They also reported the isolation of the dihydronaphthol
4 (20%) as unexpected byproduct during a hydrogenolysis
of the adduct.3
The starting acetoxyaldehydes 7 (88%) and 8 (89%)
were prepared by a one-pot procedure from corresponding
aldehydes 5 and 6, respectively.7 Initially, we attempted
to synthesize the dihydronaphthol 11 from the acetoxy-
aldehyde 7 as a model. Treatment of 7 with dimethyl
maleate in the presence of a catalytic amount of TFA in
toluene at 70 °C led to a formation of a complicated
mixture of products containing the dihydronaphthol 11
(10%), the naphthalene 12 (10%), and unidentified byprod-
ucts. When this reaction was carried out without added
solvent, the desired 11 was obtained in 90% yield with
no 12 detected.8 The trans relationship between H3-H4
of 11 is consistent with the mode of formation (vide infra)
and based on the observed large coupling constant (J 3,4
) 8.0 Hz) in the 1H NMR spectrum. For cis-dihy-
dronaphthols, this coupling constant is 4.1-5.0 Hz.4 The
selective formation of the trans compound 11 could be
explained by acid-catalyzed cleavage of the oxygen bridge
In the course of synthetic studies searching for biologi-
cally active aryltetralin lignan derivatives, the need for
a practical synthesis of (()-isopicropodophyllin (2) and
(()-isopodophyllotoxin (3) became apparent. We envi-
sioned that the dihydronaphthol 4 could serve as a
versatile synthetic intermediate for the synthesis of
aryltetralin lignans, provided 4 is readily accessible. The
(1) (a) Rao, C. B. S. Chemistry of Lignans; Andhra Univ. Press:
India, 1978. (b) Ayres, D. C.; Loike, J . D. Lignans, Cambridge Univ.
Press: Cambridge, 1990. (c) Yalowich, J . D. ; Fry, D. W.; Goldman, T.
D. Cancer Res. 1982, 42, 3648 and references cited therein. (d) Kimura,
M.; Suzuki, J .; Yamada, T.; Yoshizaki, M.; Kikuchi, T.; Kadota, S.;
Matsuda, S. Planta Med. 1985, 291.
(2) (a) Ward, R. S. Chem. Soc. Rev. 1982, 11, 75. (b) Ward, R. S.
Tetrahedron 1990, 46. 5029. (c) Ogiku, T; Yoshida, S.; Kuroda, T.;
Takahashi, M.; Ohmizu, H.; Iwasaki, T. Bull. Chem. Soc. J pn. 1992,
65, 3495. (d) Ogiku, T; Yoshida, S.; Kuroda, T.; Ohmizu, H.; Iwasaki,
(4) Caple, R.; Chen, G. M.-S.; Nelson J . D. J . Org. Chem. 1971, 36,
2874.
(5) Wittig, G.; Pohmer, L. Chem. Ber. 1956, 89, 1334.
(6) Recently, we have reported the synthesis of heteroaromatic
arylnaphthalene lignans from acetoxyaldehydes via heteroaromatic
arylisobenzofurans. Kuroda, T.; Takahashi, M.; Ogiku, T.; Ohmizu, H.;
Kondo, K.; Iwasaki, T. J . Chem. Soc., Chem. Commun. 1991, 1635.
Kuroda, T.; Takahashi, M.; Ogiku, T.; Ohmizu, H.; Nishitani, T.; Kondo,
K.; Iwasaki, T. J . Org. Chem. 1994, 59, 7353.
T. Synlett 1992, 651. For
podophyllotoxin and related compounds, see Ward, R. S. Synthesis
1992, 719.
a
recent review for the synthesis of
(7) (a) Comins, D. L.; Brown, J . D. J . Org. Chem. 1984, 49, 1078.
(b) Comins, D. L.; Brown, J . D. Tetrahedron Lett. 1981, 22, 4213.
(8) The use of p-toluenesulfonic acid in lieu of TFA caused
a
(3) Forsey, S. P.; Rajapaksa, D.; Taylor, N. J .; Rodrigo, R. J . Org.
Chem. 1989, 54, 4280.
considerable decrease in yield of 11 (38%) with concomitant formation
of 12 (9%).
S0022-3263(96)00938-3 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 26, 1996 9561
Sch em e 1
Sch em e 2
of the endo adduct 10 followed by deprotonation.9 The
preferential formation of endo adducts has previously
been reported in the acid-catalyzed Diels-Alder reaction
of isobenzofurans with dimethyl maleate.10 Similarly,
treatment of the acetoxyaldehyde 8 with dimethyl male-
ate under the same conditions gave the desired dihy-
dronaphthol 4 in 88% yield. In a separate experiment,
the dihydronaphthol 11 did aromatize to give naphtha-
lene 12 (82%) by treatment with a catalytic amount of
boron trifluoride etherate in the presence of dimethyl
maleate at room temperature, as reported in the case of
1-hydroxy-1,2-dihydronaphthalenes.4 This result clearly
demonstrates the importance of carefully selecting the
reaction conditions.
deliver hydrogen preferentially from the same side as
hydroxyl group11 to afford tetralin 14. Contrary to
expectation, hydrogenation of 4 with 10% palladium on
charcoal (1 atm H2, MeOH-EtOAc, 25 °C) gave a mixture
of tetralins 14 and 1512 (1:2 ratio of 14 and 15) in 95%
yield (Table 1, entry 1). The cationic rhodium complex,
[Rh(nbd)(diphos-4)]BF4,15 has been employed for directed
hydrogenation of cyclic homoallylic alcohols. Coordina-
tion of a proximal hydroxy group with the catalyst can
lead to the delivery of hydrogen to the unsaturated bond
in a syn fashion.11a Therefore, this methodology appeared
We next attempted to synthesize the tetralins 14 and
16 via stereocontrolled hydrogenation of 4 (Scheme 2,
Table 1). Catalytic hydrogenation of 4 was expected to
(9) The formation of 11 rather than the 1-hydroxy compound A can
be attributed to the greater stability of the transient diaryl carbocation
B compared to the monoaryl one C. See, for example : March, J .
Advanced Organic Chemistry, 4th ed.; Wiley-Interscience: New York,
1992; pp 165-174.
(11) (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993,
93, 1307. (b) Evans, D. A.; Morrissey, M. M. J . Am. Chem. Soc. 1984,
106, 3866. (c) Evans, D. A.; Morrissey, M. M.; Dow, R. L. Tetrahedron
Lett. 1985, 26, 6005. (d) Satoh, T.; Suzuki, S.; Suzuki, Y. Chem. Pharm.
Bull. 1971, 19, 817. (e) For the hydroxyl-directed hydrogenation using
metal hydrides, see: Iio, H.; Isobe, M.; Kawai, T.; Goto, T. J . Am. Chem.
Soc. 1979, 101, 6076. Salomon, R. G.; Sachinvala, N. D.; Raychaudhuri,
S. R.; Miller, D. B. J . Am. Chem. Soc. 1984, 106, 2211. Hanzawa, Y.;
Kawagoe, K.; Kawada, K.; Kobayashi, Y. Chem. Pharm. Bull. 1985,
33, 2579.
(12) The stereochemistry of 14-16 was determined by 1H NMR
spectroscopy. The coupling constants of these compounds compare very
well with those of similar tetralins.3,13,14
(13) Gupta, A.; Rodrigo, R. J . Chem. Soc., Chem. Commun. 1989,
959.
(14) Maddafold, S. P.; Charlton, J . L. J . Org. Chem. 1993, 58, 4132.
(15) nbd ) norbornadiene, diphos-4 ) 1,4-bis(diphenylphosphino)-
butane. For previous examples of the hydroxyl-directed hydrogenation
using [Rh(nbd)(diphos-4)]BF4, see ref 11a-c.
(10) Meegalla, S. K.; Rodrigo, R. J . Org. Chem. 1991, 56, 1882.

9562 J . Org. Chem., Vol. 61, No. 26, 1996
Ta ble 1. Red u ction of Dih yd r on a p h th ol 4
Notes
product
entry
reagent
10% Pd/C
[Rh(nbd)(diphos-4)]BF4
NiCl2‚6H2O/NaBH4
solvent
time (h)
(yield,a %)
1
2
3
MeOH-CH2Cl2
CH2Cl2
MeOH-THF
1
20
20
14 (32),15 (63)
14 (81), 15 (4)b
16 (87)c
Isolated yield. Dihydronaphthol 4 was recovered in 5% yield. c Naphthalene 13 was obtained in 5% yield.
a
b
LiEt3BH were purchased from Aldrich Chemical Co. Butyl-
lithium was the 1.6 M solution in hexane supplied by Asia
Lithium Co.
Sch em e 3
2-(r-Ace t oxy-3,4-d im e t h oxyb e n zyl)-3,4,5-t r im e t h oxy-
ben za ld eh yd e (7). To a solution of N,N,N′-trimethylethylene-
diamine (4.6 mL, 36 mmol) in THF (100 mL) was added BuLi
(20.6 mL, 33 mmol) at -78 °C. After 5 min, 3,4,5-trimethoxy-
benzaldehyde (5) (5.88 g, 30 mmol) in THF (30 mL) was added,
and the mixture was stirred at -78 °C for an additional 15 min.
Diisopropylamine (4.7 mL, 33 mmol) and BuLi (37.5 mL, 60
mmol) were added, and the flask was sealed and put in a freezer
(-20 °C) for 6 h. To this solution was added 3,4-dimethoxybenz-
aldehyde (4.98 g, 30 mmol) in THF (50 mL) at -78 °C, and the
mixture was stirred for an additional 1 h. To this solution was
added acetic anhydride (6.12 g, 60 mmol), and the mixture was
allowed to warm to room temperature during 1 h. The mixture
was poured into vigorously stirred cold water (200 mL) and
extracted with EtOAc. The organic extract was washed with
brine and dried over MgSO4. The mixture was filtered, and the
filtrate was concentrated under reduced pressure. The residue
was purified by silica gel chromatography (hexane:EtOAc ) 4:1)
to give a white solid. Recrystallization from isopropyl ether gave
7 (10.67 g, 88% yield) as colorless crystals. Mp 96-98 °C. IR
(Nujol) 1740, 1680 cm-1 1H NMR (CDCl3) δ 2.15 (s, 3H), 3.83
.
(s, 3H), 3.85 (s, 3H), 3.93 (s, 3H), 3.94 (s, 3H), 3.99 (s, 3H), 6.64-
6.90 (m, 3H), 7.37 (s, 1H), 7.64 (s, 1H), 10.29 (s, 1H). MS (m/z)
404 (M+). Anal. Calcd for C21H24O8: C, 62.37; H, 5.98. Found:
C, 62.56; H, 5.91.
to be very attractive for the selective hydrogenation of
4. As expected, hydrogenation of 4 with [Rh(nbd)(diphos-
4)]BF4 (50 atm H2, CH2Cl2, 25 °C) produced stereoselec-
tively 14 (20:1 ratio of 14 and 15) in 81% yield (entry 2).
2-(r-Acet oxy-3,4,5-t r im et h oxyb en zyl)-4,5-(m et h ylen e-
d ioxy)ben za ld eh yd e (8). To a solution of morpholine (3.13 g,
36 mmol) in THF (100 mL) was added BuLi (20.6 mL, 33 mmol)
at -78 °C. After 5 min, 2-bromo-4,5-(methylenedioxy)benzal-
dehyde (6.87 g, 30 mmol) in THF (30 mL) was added, and the
mixture was stirred at -78 °C for an additional 15 min. To this
solution was added BuLi (20.6 mL, 33 mmol) at -78 °C, and
the mixture was stirred for an additional 15 min. To this
solution was added 3,4,5-trimethoxybenzaldehyde (5.88 g, 30
mmol) in THF (50 mL) at -78 °C, and the mixture was stirred
for an additional 1 h. To this solution was added acetic
anhydride (6.12 g, 60 mmol), and the mixture was allowed to
warm to room temperature during 1 h. The mixture was poured
into vigorously stirred cold water (200 mL) and extracted with
EtOAc. The organic extract was washed with brine and dried
over MgSO4. The mixture was filtered, and the filtrate was
concentrated under reduced pressure. The residue was purified
by silica gel chromatography (hexane:EtOAc ) 4:1) to give a
white solid. Recrystallization from isopropyl ether gave 8 (10.35
g, 89% yield) as colorless crystals. Mp 90-92 °C. IR (Nujol)
16
When 4 was hydrogenated with NiCl2‚6H2O-NaBH4
(MeOH-THF, 25 °C) the epimeric tetralin 1612 was
obtained in 87% yield along with the aromatized product
13 (5%) (entry 3).17 No further attempts at optimizing
the above hydrogenation conditions were attempted.
The tetralins 14 and 16 thus obtained were converted
to (()-isopicropodophyllin (2) and (()-isopodophyllotoxin
(3), respectively, upon reaction with LiEt3BH followed by
NaH (Scheme 3).3 The overall yield of 2 starting with
piperonal was 44% and for 3 was 45%.
In summary, we have demonstrated that dihydronaph-
thols can be obtained in one step and good yields from
acetoxyaldehydes. We have also demonstrated the utility
of dihydronaphthol 4 in an efficient synthesis of conge-
ners 2 and 3 of podophyllotoxin. Further synthetic uses
of the dihydronaphthols made available by this method-
ology will be reported in future papers.
1740, 1680 cm-1
.
1H NMR (CDCl3) δ 2.17 (s, 3H), 3.82 (br s,
9H), 6.09 (s, 2H), 6.54 (s, 2H), 7.06 (s, 1H), 7.33 (s, 1H), 7.57 (s,
1H), 10.13 (s, 1H). MS (m/z) 388 (M+). Anal. Calcd for
Exp er im en ta l Section
C
20H20O8: C, 61.85; H, 5.19. Found: C, 61.76; H, 5.33.
Rea ction s of Acetoxya ld eh yd es w ith Dim eth yl Ma lea te.
Gen er a l. Melting points were determined on a capillary
melting point apparatus and are uncorrected. 1H NMR spectra
were obtained at 200 MHz. Chemical shifts are reported in ppm
(δ) using Me4Si as standard. Elemental analyses were carried
out in this laboratory. Column chromatography was performed
with silica gel (70-230 mesh). [Rh(nbd)(diphos-4)]BF4 and
Rea ction of 7 in Tolu en e. To a solution of acetoxyaldehyde 7
(808 mg, 2 mmol) and dimethyl maleate (1.3 mL, 10 mmol) in
toluene (10 mL) was added TFA (10 µL), and the mixture was
heated for 2 h at 70 °C. The reaction mixture was concentrated
under reduced pressure. The residue was purified by flash
chromatography [silica gel (230-400 mesh), hexane:EtOAc )
2:1]. Recrystallization from EtOAc-hexane gave the dihy-
dronaphthol 11 (98 mg, 10% yield) and the naphthalene 12 (94
mg, 10% yield) as colorless crystals.
(16) (a) Satoh, T.; Nanba, K.; Suzuki, S. Chem. Pharm. Bull. 1971,
19, 817. (b) Abe, N.; Fujisaki, F.; Sumoto, K.; Miyano, S. Chem. Pharm.
Bull. 1991, 39, 1167. (c) Miyano, S.; Abe, N.; Fujisaki, F.; Sumoto, K.
Heterocycles 1987, 26, 1813.
Dim eth yl (3,4-tr a n s)-4-Hyd r oxy-6,7,8-tr im eth oxy-1-(3,4-
(17) A possible explanation for the formation of 16 involves initial
formation of 14 followed by epimerization at C-2 under the reaction
d im eth oxyp h en yl)-3,4-d ih yd r on a p h th a len e-2,3-d ica r boxy-
la te (11). Mp 144-145 °C. IR (Nujol) 3420, 1740, 1695 cm-1
.
conditions. The formation of cis hydrogenated products with Ni2+/BH4
-
1H NMR (CDCl3) δ 3.16 (s, 3H), 3.30-4.00 (m, 2H), 3.46 (s, 3H),
system16 and a facile epimerization at C-23 have previously been
reported.
3.68 (s, 3H), 3.74 (s, 3H), 3.84 (s, 3H), 3.88 (s, 3H), 3.91 (s, 3H),

Notes
J . Org. Chem., Vol. 61, No. 26, 1996 9563
5.02 (d, J ) 8.0 Hz, 1H), 6.70-6.90 (m, 4H). MS (m/z) 488 (M+).
Anal. Calcd for C25H28O10: C, 61.47; H, 5.78. Found: C, 61.72;
H, 5.56.
4)]BF4 (14 mg, 0.02 mmol) were dissolved in CH2Cl2 (10 mL)
and hydrogenated at the pressure of 50 atm and 25 °C for 5 h.
The catalyst was filtered off, and the filtrate was concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane:EtOAc ) 2:1) and crystallized
from hexane to give 14 (162 mg, 81% yield) and 15 (8 mg, 4%
yield) as colorless needles.
Dim eth yl 1-(3,4-Dim eth oxyph en yl)-6,7,8-tr im eth oxyn aph -
th a len e-2,3-d ica r boxyla te (12). Mp 215-217 °C. IR (Nujol)
1740, 1695 cm-1 1H NMR (CDCl3) δ 3.30 (s, 3H), 3.56 (s, 3H),
.
3.84 (s, 3H), 3.90 (s, 3H), 3.93 (s, 3H), 3.94 (s, 3H), 4.03 (s, 3H),
6.86 (s, 3H), 7.10 (s, 1H), 8.45 (s, 1H). MS (m/z) 470 (M+). Anal.
Calcd for C25H26O9: C, 63.82; H, 5.57. Found: C, 63.72; H, 5.66.
Rea ction of 7 w ith ou t Ad d ed Solven t. To a mixture of
dimethyl maleate (10 mL) and TFA (5 µL) was added dropwise
a solution of acetoxyaldehyde 7 (808 mg, 2 mmol) in dimethyl
maleate (5 mL) over a period of 2.5 h at 70 °C. The mixture
was then heated for 1.5 h at 70 °C and concentrated under
reduced pressure. The residue was purified by flash chroma-
tography [silica gel (230-400 mesh), hexane:EtOAc ) 2:1] to
give a white solid. Recrystallization from Et2O gave the dihy-
dronaphthol 11 (878 mg, 90% yield) as colorless crystals.
R ea ct ion of 8. Dim et h yl (3,4-tr a n s)-4-H yd r oxy-6,7-
(m et h ylen ed ioxy)-1-(3′,4′,5′-t r im et h oxyp h en yl)-3,4-d ih y-
d r on a p h th a len e 2,3-Dica r boxyla te (4). The reaction of 8
with dimethyl maleate was performed as described in the
preparation of 11 (without added solvent). The reaction mixture
was concentrated, and the mixture was purified by flash
chromatography [silica gel (230-400 mesh), hexane:EtOAc )
2:1] to give a white solid. Recrystallization from Et2O gave the
dihydronaphthol 4 (831 mg, 88% yield) as colorless crystals. Mp
Hyd r ogen a tion of 4 w ith NiCl2‚6H2O-Na BH4. To a
stirred solution of the dihydronaphthol (4) (100 mg, 0.2 mmol)
and NiCl2‚6H2O (95 mg, 0.4 mmol) in MeOH (1 mL) and THF
(5 mL) was added NaBH4 (31 mg, 0.81 mmol) in small portions
over a period of 10 min at 0 °C. After addition of NaBH4, the
mixture was stirred for 4 h at room temperature. The black
precipitate was filtered off and the filtrate was acidified with
10% aqueous HCl. The solvent was removed under reduced
pressure, and the residue was diluted with H2O. After extraction
with Et2O, the organic phase was dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was
purified by silica gel chromatography (hexane:EtOAc ) 2:1) to
give the tetralin 16 as a white solid (87 mg, 87% yield) along
with the aromatized product 13 (5 mg, 5% yield). Recrystalli-
zation of 16 from isopropyl ether gave colorless crystals.
Dim eth yl (1,2-tr a n s,2,3-tr a n s,3,4-tr a n s)-4-Hyd r oxy-6,7-
(m et h ylen ed ioxy)-1-(3,4,5-t r im et h oxyp h en yl)-1,2,3,4-t et -
r a h yd r on a p h th a len e-2,3-d ica r boxyla te (16). Mp 174-175
°C. IR (Nujol) 3420, 1740, 1695 cm-1 1H NMR (CDCl3) δ 3.40
.
(dd, J ) 9.4, 12.5 Hz, 1H), 3.50-3.65 (m, 1H), 3.51 (s, 3H), 3.71
(s, 3H), 3.83 (s, 6H), 3.92 (s, 3H), 4.54 (d, J ) 5.7 Hz, 1H), 4.83
(d, J ) 2.8 Hz, 1H), 4.99 (dd, J ) 2.8, 9.4 Hz, 1H), 5.96 (s, 2H),
6.40 (s, 2H), 6.96 (s, 1H), 7.24 (s, 1H). MS (m/z) 474 (M+). Anal.
Calcd for C24H26O10: C, 60.76; H, 5.52. Found: C, 60.59; H, 5.71.
172-174 °C (lit.3 mp 173-175 °C). Anal. Calcd for C24H24O10
:
C, 61.02; H, 5.12. Found: C, 61.12; H, 5.06. The spectral data
of this compound were identical in all respects with those
described previously.3
Rea ction of th e Dih yd r on a p h th ol (11) w ith Bor on Tr i-
flu or id e Eth er a te. To a suspension of the dihydronaphthol
11 (140 mg, 0.29 mmol) in dimethyl maleate (10 mL) was added
boron trifluoride etherate (47% solution in Et2O, 10 µL), and
the mixture was stirred at room temperature for 2 h. The
reaction mixture was concentrated under reduced pressure, and
the residue was purified by silica gel chromatography (hexane:
EtOAc ) 4:1) to give a white solid. Recrystallization from
EtOAc-hexane gave the naphthalene 12 (110 mg, 82% yield)
as colorless crystals.
Heter ogen eou s Ca ta lytic Hyd r ogen a tion of 4. A solution
of the dihydronaphthol 4 (100 mg, 0.20 mmol) in EtOAc (15 mL)
and MeOH (5 mL) was hydrogenated over 10% Pd-C (100 mg)
at atmospheric pressure and 25 °C for 5 h. The catalyst was
filtered off, and the filtrate was concentrated under reduced
pressure. The residual mixture was separated by silica gel
column chromatography (hexane:EtOAc ) 2:1). Crystallization
from hexane gave 14 (32 mg, 32% yield) and 15 (63 mg, 63%
yield) as colorless needles.
Dim et h yl
p h en yl)-n a p h th a len e-2,3-d ica r boxyla te (13). Mp 216-217
°C. IR (Nujol) 1730, 1690 cm-1 1H NMR (CDCl3) δ 3.66 (s, 3H),
6,7-(Met h ylen ed ioxy)-1-(3,4,5-t r im et h oxy-
.
3.83 (s, 6H), 3.94 (s, 6H), 6.08 (s, 2H), 6.55 (s, 2H), 6.93 (s, 1H),
7.23 (s, 1H), 8.40 (s, 1H). MS (m/z) 454 (M+). Anal. Calcd for
C
24H22O9: C, 63.43; H, 4.88. Found: C, 63.59; H, 4.71.
(()-Isop icr op od op h yllin (2). A solution of 14 (104 mg, 0.22
mmol) in THF (5 mL) was cooled to 0 °C, and LiEt3BH (1.0 M
solution in THF, 0.73 mL) was added. After 1 h, aqueous acetic
acid (50%) was added until the yellow color disappeared. Water
(10 mL) was then added, and the mixture was extracted with
CH2Cl2. The organic extract was dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was dissolved
in MeOH/THF (5 mL, 1:1), and water (1 mL) was added. The
mixture was stirred for 12 h. The solvents were largely removed
under reduced pressure, and the residue was extracted with
EtOAc. The organic extract was washed with water, and the
solvent was removed under reduced pressure to give a solid (63.5
mg). To a solution of this solid in THF (25 mL) was added NaH
(60%, 18 mg, 0.44 mmol). The mixture was stirred for 1 h at 25
°C. Cold water (15 mL) was added, and the volume was reduced
to approximately 15 mL by evaporation. The solution was
extracted with CH2Cl2, dried over MgSO4, and concentrated to
dryness under reduced pressure. The residue was recrystallized
from CH2Cl2-MeOH to give 2 (50 mg, 77% yield). Mp 190-191
°C (lit.3 mp 191-192 °C). Anal. Calcd for C22H22O8: C, 63.76;
H, 5.35. Found: C, 63.59; H, 5.51. The spectral data of this
compound were identical in all respects with those described
previously.3
Dim eth yl (1,2-cis,2,3-cis,3,4-tr a n s)-4-Hyd r oxy-6,7-(m eth -
yle n e d ioxy)-1-(3,4,5-t r im e t h oxyp h e n yl)-1,2,3,4-t e t r a h y-
d r on a p h th a len e-2,3-d ica r boxyla te (14). Mp 173-175 °C
(lit.3 mp 174-175 °C). Anal. Calcd for C24H26O10: C, 60.75; H,
5.52. Found: C, 60.81; H, 5.55. The spectral data of this
compound were identical in all respects with those described
previously.3
Dim et h yl
(1,2-cis,2,3-tr a n s,3,4-tr a n s)-4-H yd r oxy-6,7-
(m et h ylen ed ioxy)-1-(3,4,5-t r im et h oxyp h en yl)-1,2,3,4-t et -
r a h yd r on a p h th a len e-2,3-d ica r boxyla te (15). Mp 171-173
°C. IR (Nujol) 3420, 1740, 1695 cm-1 1H NMR (CDCl3) δ 2.86
.
(d, J ) 4.6 Hz, 1H), 3.40 (dd, J ) 9.4, 12.5 Hz, 1H), 3.46 (s, 3H),
3.53-3.65 (m, 1H), 3.74 (s, 3H), 3.84 (s, 3H), 3.88 (s, 3H), 3.91
(s, 3H), 4.54 (d, J ) 5.7 Hz, 1H), 4.85 (dd, J ) 4.6, 9.4 Hz, 1H),
5.93 (br s, 2H), 6.38 (s, 3H), 7.17 (s, 1H). MS (m/z) 474 (M+).
Anal. Calcd for C24H26O10: C, 60.76; H, 5.52. Found: C, 60.81;
H, 5.55.
(()-Isop od op h yllotoxin (3). The tetralin 16 was trans-
formed to 3 by the same method as above (47 mg, 73% yield).
Mp 270-272 °C (lit.3 mp 272-273 °C). Anal. Calcd for
C
22H22O8: C, 63.76; H, 5.35. Found: C, 63.59; H, 5.51. The
spectral data of this compound were identical in all respects with
those described previously.3
Hyd r ogen a tion of 4 w ith a Ca tion ic Rh od iu m Ca ta lyst.
The dihydronaphthol 4 (200 mg, 0.4 mmol) and [Rh(nbd)(diphos-
J O9609384