First Stereocontrolled Syntheses of Unsymmetrically Substituted Bislactone Lignans: Stereocontrolled Syntheses of Four Possible Isomers of Methyl 4,8-Dioxoxanthoxylol

Article abstract of DOI:10.1021/jo961733y

An efficient method for stereocontrolled syntheses of the unsymmetrically substituted bislactone subgroup of the furofuran lignan has been developed based on a stereoselective aldol reaction of the acid anhydride 8 or 9 and an aromatic aldehyde employing

Full text of DOI:10.1021/jo961733y

1310
J . Org. Chem. 1997, 62, 1310-1316
F ir st Ster eocon tr olled Syn th eses of Un sym m etr ica lly Su bstitu ted
Bisla cton e Lign a n s: Ster eocon tr olled Syn th eses of F ou r P ossible
Isom er s of Meth yl 4,8-Dioxoxa n th oxylol
Shin-ichi Yoshida, Tsuyoshi Ogiku, Hiroshi Ohmizu,* and Tameo Iwasaki
Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89, Kashima,
Yodogawa, Osaka 532, J apan
Received September 10, 1996X
An efficient method for stereocontrolled syntheses of the unsymmetrically substituted bislactone
subgroup of the furofuran lignan has been developed based on a stereoselective aldol reaction of
the acid anhydride 8 or 9 and an aromatic aldehyde employing methyl 4,8-dioxoxanthoxylol (1a ),
4,8-dioxofargesin (1b), methyl 4,8-dioxopiperitol (2a ) and their isomer 3a as the representative
examples of the axial-equatorial 1, diequatorial 2, and diaxial 3 types of this series.
In tr od u ction
Lignans of the furofuran series I (4,8-dioxo-3,7-
dioxabicyclo[3.3.0]octane), II (4-oxo-3,7-dioxabicyclo[3.3.0]-
octane) and III (3,7-dioxabicyclo[3.3.0]octane) are of
considerable interest because of their wide range of
biological activities (Figure 1).1 Some of the naturally
occurring bislactones (series I) have been reported to
modulate the functions of central nervous systems by
inhibition of catechol-O-methyltransferase, dopamine
â-hydroxylase, and dopa decarboxylase (Figure 1).2 Mono-
lactone furofurans (series II) and simple furofurans
(series III) have been also known to exhibit inhibition
activity of phosphodeesterase and antagonistic activity
of platelet aggregation factor.3 Although much effort has
been devoted to developing an efficient method for
syntheses of the furofuran series of lignans and several
ingenious ones have been reported,4 only a little attention
has been devoted to syntheses of the bislactone subgroup
I; some nonstereocontrolled ones including those based
on the oxidative dimerization of the cinnamic acid
derivatives,5 the reaction of 2,5-bis(trimethylsilyloxy)-
furans with benzaldehydes,6 and aldol reaction of
N,N,N′,N′-tetraethylsuccindiamide and aromatic alde-
hydes have been reported.7 In connection with our
synthetic studies in search of new compounds having
intriguing biological activities from lignans,8 we have
been interested in synthesis of the bislactone subgroup
F igu r e 1.
of furofuran lignans. In this paper, we report the full
account of our efforts to stereocontrolled syntheses of this
group of lignans.9
Resu lts a n d Discu ssion
There are four stereoisomers in this series of lignans
having two different aryl groups, which are exemplified
by 1a , 1b, 2a , and 3a (Figure 2). We selected these four
compounds as the representative examples of these
stereoisomers and envisaged that they would be synthe-
sized via the key intermediates 4-7, respectively, based
on the strategy illustrated in Scheme 1. The four con-
tiguous carbon centers of these key intermediates would
be stereochemically defined based on (i) the stereoselec-
tive reduction of the carbonyl group at C-1 of keto ester
10, which defines the relative stereochemistry between
C-1 and C-2; (ii) the stereoselective aldol reaction of the
acid anhydride 8 or 9 with veratraldehyde, which defines
the relative stereochemistry among C-2, C-3, and C-4.
Moreover, the alkoxy anion generated in the aldol reac-
tion was expected to subsequently attack the carbonyl
carbon atom of the acid anhydride intramolecularly to
afford the γ-lactone skeleton (Scheme 1).
X Abstract published in Advance ACS Abstracts, February 1, 1997.
(1) Reviews: (a) Chemistry of lignans; Rao, C. B. S., Ed.; Andhra
Univ. Press: India, 1978. (b) Lignans; Ayres, D. C.; Loike, J . D., Ed.;
Cambridge University Press: New York, 1990. (c) Ward, R. S. Chem.
Soc. Rev. 1982, 11, 75.
(2) Kumada, Y.; Naganawa, H.; Iimura, H.; Matsuzaki, M.; Takeu-
chi, T.; Umezawa, H. J . Antibiot. 1976, 882.
(i) P r ep a r a tion of th e Key In ter m ed ia tes 8 a n d
9. According to the strategy, the intermediate 10 was
first synthesized. The Michael addition reaction of the
anion generated by treatment of the cyanohydrin 118d
(3) MacRae, W. D.; Towers, G. H. N. Phytochemistry 1984, 1207.
(4) (a) Pelter, A.; Ward, R. S.; Watson, D. J .; Collins, P. J . Chem.
Soc., Perkin Trans. 1 1982, 175. (b) Pelter, A.; Ward, R. S.; Collins,
P.; Venkateswarlu, R.; Kay, I. T. J . Chem. Soc., Perkin Trans. 1 1985,
587. (c) Till, C. P.; Whiting, D. J . Chem. Soc., Chem. Commun. 1984,
590. (d) Stevens, D. R.; Whiting, D. A. Tetrahedron Lett. 1986, 27,
4629. (e) Stevens, D. R.; Till, C. P.; Whiting, D. A. J . Chem. Soc., Perkin
Trans. 1 1992, 185. (f) Bradley, H. M.; Knight, D. W. J . Chem. Soc.,
Chem. Commun. 1991, 1641. (g) Takano, S.; Ohkawa, T.; Tamori, S.;
Satoh, S.; Ogasawara, K. J . Chem. Soc., Chem. Commun. 1988, 189.
(h) Takano, S.; Samizu, K.; Ogasawara, K. Synlett 1993, 785. (i)
Suginome, H.; Orito, K.; Yorita, K.; Ishikawa, M.; Shimoyama, N.;
Sasaki, T. J . Org. Chem. 1995, 60, 3052.
(5) (a) Cartwright, N. J .; Haworth, R. D. J . Chem. Soc. 1944, 535.
(b) Iguchi, M.; Nishiyama, A.; Eto, H.; Terada, Y.; Yamamura, S. Chem.
Lett. 1979, 1397.
(6) Brownbridge, P.; Chan, T.-H. Tetrahedron Lett. 1980, 21, 3427.
(7) Mahalanabis, K. K.; Mumtaz, M.; Snieckus, V. Tetrahedron Lett.
1982, 23, 3975.
(8) (a) Ogiku, T.; Seki, M.; Takahashi, M.; Ohmizu, H.; Iwasaki, T.
Tetrahedron Lett. 1990, 31, 5487. (b) Ogiku, T.; Yoshida, S.; Kuroda,
T.; Ohmizu, H.; Iwasaki, T. Synlett 1992, 651. (c) Ogiku, T.; Yoshida,
S.; Takahashi, M.; Kuroda, T.; Ohmizu, H.; Iwasaki, T. Bull. Chem.
Soc., J pn. 1992, 65, 3495. (d) Ogiku, T.; Yoshida, S.; Ohmizu, H.;
Iwasaki, T. J . Org. Chem. 1995, 60, 4585. (e) Ogiku, T.; Yoshida, S.;
Takahashi, M.; Kuroda, T.; Ohmizu, H.; Iwasaki, T. Tetrahedron Lett.
1992, 33, 4473. (f) Ogiku, T.; Yoshida, S.; Takahashi, M.; Kuroda, T.;
Ohmizu, H.; Iwasaki, T. Tetrahedron Lett. 1992, 33, 4477. (g) Ogiku,
T.; Yoshida, S.; Ohmizu, H.; Iwasaki, T. J . Org. Chem. 1995, 60, 1148.
(9) (a) Yoshida, S.; Ogiku, T.; Ohmizu, H.; Iwasaki, T. Tetrahedron
Lett. 1995, 36, 1455. (b) Yoshida, S.; Ogiku, T.; Ohmizu, H.; Iwasaki,
T. Tetrahedron Lett. 1995, 36, 1459.
S0022-3263(96)01733-1 CCC: $14.00 © 1997 American Chemical Society

Syntheses of Unsymmetrically Substituted Bislactone Lignans
J . Org. Chem., Vol. 62, No. 5, 1997 1311
Sch em e 1
F igu r e 2.
with LDA to dimethyl maleate in toluene at -70 °C
followed by treatment of the resulting adduct with
tetrabutylammonium fluoride-acetic acid (1:1) in THF
at room temperature afforded the benzoyl succinate 10
in 85% yield (Scheme 2).
Reduction of the carbonyl group of 10 was next
examined (Table 1). Reduction of 10 with NaBH4 in
MeOH at 0 °C provided the anti-hydroxy ester 12 in 55%
yield along with the trans-lactone 13 (5%) generated via
the initially yielded 14 (run 1). The corresponding cis-
lactone was not produced in this reaction probably due
to the unfavorable steric repulsion between the aryl and
the methoxycarbonyl groups. A satisfactory result was
obtained in the use of L-selectride in toluene at -70 °C,
in which 12 was isolated in 92% yield as a sole product
(run 2). This anti-selectivity would be explained by the
Felkin-Ahn model illustrated in Figure 3, in which the
hydride attacks the carbonyl group from the opposite side
of the methoxycarbonyl group.
Sch em e 2
Treatment of 12 with TBDMSCl and imidazole in DMF
followed by saponification of the diester 15 gave the
diacid 16 in 81% yield. The diacid 16 was stirred in acetic
anhydride at 60 °C for 30 min to afford the key inter-
mediate 8 in 96% yield (Scheme 3).
On the other hand, Pd-catalyzed hydrogenation of 10
was examined in order to obtain the syn-hydroxy ester
14 selectively, because the Pd-catalyzed reduction of the
â-keto ester has been reported to afford a syn-hydroxy
ester in a highly stereoselective manner.10 However,
reduction of 10 under the similar conditions as those of
the reported one gave unexpectedly the anti-hydroxy
ester exclusively (run 3). Thus, an alternative method
was examined. Nakata et al. have reported that the zinc-
chelated reduction of the â-keto ester proceeded in a
highly stereoselective manner to afford the syn-isomer
(erythro-isomer) in good yield.11 The method was applied
to the reduction of 10, and the desired trans-lactone 13
was obtained in 79% yield along with the isomer 12 in
6% yield (run 4). We considered that the selectivity was
(10) Bolhofer, W. A. J . Am. Chem. Soc. 1953, 75, 4469.
(11) Nakata, T.; Oishi, T. Tetrahedron Lett. 1980, 21, 1641.

1312 J . Org. Chem., Vol. 62, No. 5, 1997
Yoshida et al.
Ta ble 1. Red u ction of 10
Sch em e 4
yield (%)a
12 13
run
reagent
NaBH4
L-Selectride
H2, Pd-C
Zn(BH4)2
solvent
temp (°C)
1
2
3
4
MeOH
toluene
AcOH
ether
0
-70
25
55
92
88
6
5
-
-
-20-0
79
a
Isolated yield.
Sch em e 5
F igu r e 3.
Sch em e 3
not complete but acceptable and turned our focus on con-
version of 13 into the corresponding syn-hydroxy ester.
Usual treatment of 13 with NaOMe in methanol
resulted in an elimination reaction to give the undesired
half ester 17 quantitatively. This result indicated that
the desired ring opening reaction of the γ-lactone 13
required a nucleophile which is less basic than NaOMe.
Thus, the aluminum-mediated thioesterification was next
examined.12
Treatment of 13 with dimethylaluminum tert-butyl
sulfide in CH2Cl2 at 0 °C followed by protection of the
hydroxyl group with a TBDMS group afforded 19 via 18
in 63% yield. The thioester 19 was saponified followed
by treatment of the resulting diacid 20 with acetic
anhydride to give the key intermediate 9 in 90% yield
(Scheme 4).13
(ii) Ald ol Rea ction s of th e Acid An h yd r id es 8 a n d
9 w ith Ver a tr a ld eh yd e. The aldol reactions of the acid
anhydrides 8 and 9 with veratraldehyde, the key reac-
tions of our strategy, were next examined (Schemes 5 and
6). The aldol reaction of 8 with veratraldehyde was first
carried out employing LDA as a base. However, addition
of LDA to a mixture of 8 and veratraldehyde in THF at
-50 °C gave a mixture of 21 and its isomer 22 in only
8% yield,14 the ratio of 21 to 22 being 44:56 (Table 2).
Kuwajima et al. reported that the sterically hindered
Ta ble 2. Ald ol Rea ction of 8 w ith Ver a tr a ld eh yd e
temp
(°C)
ratioa
21:22
yield (%)b
21 + 22
run
base
LDA
solvent
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
THF
THF
THF
toluene
toluene
-50
-50
44:56
47:53
62:38
56:44
81:19
8:92
8:92
6:94
5:95
8
54
71
67
77
70
85
73
82
LiHMDS
LiHMDS
NaHMDS
NaHMDS
KHMDS
KHMDS
KHMDS
KHMDS
-100
-50
-100
-50
-100
-50
-90
a
Determined by HPLC analysis of the crude reaction product.
Isolated yield as a mixture of 21 and 22.
b
alkoxide was effective as a base in the aldol reaction of
the succinic anhydride derivatives with aldehydes.15
Thus, the reaction using a metal amide of 1,1,1,3,3,3-
hexamethyldisilazane (HMDS), the amine part of which
was bulkier than that of LDA, was next examined. In
the use of LiHMDS or NaHMDS at -50 °C, the combined
yield of the products rose up to be 54% or 67%, respec-
tively, as expected, but anti-selectivity was not obtained
(run 2, 4). The anti-selectivity was found to be obtained
(12) Hatch, R. P.; Weinreb, S. M. J . Org. Chem. 1977, 42, 3960.
(13) The stereochemistry of 8 and 9 was unambiguously confirmed
by X-ray crystallographic analysis of 21 and 3a .
(14) Addition of veratraldehyde to a mixture of the acid anhydride
and LDA in THF at -50 °C did not give the coupling products at all.
(15) Minami, N.; Kuwajima, I. Tetrahedron Lett. 1977, 17, 1423.

Syntheses of Unsymmetrically Substituted Bislactone Lignans
J . Org. Chem., Vol. 62, No. 5, 1997 1313
Ta ble 3. Ald ol Rea ction of 9 w ith Ver a tr a ld eh yd e
Sch em e 6
temp
(°C)
ratioa
25:26
yield (%)b
25 + 26
run
base
solvent
1
2
3
4
LiHMDS
NaHMDS
KHMDS
KHMDS
THF
THF
THF
toluene
-100
-100
-100
-90
77:23
79:21
16:84
13:87
66
71
75
81
a
Determined by HPLC analysis of the crude reaction product.
b
Isolated yield as a mixture of 25 and 26.
when the reaction was carried out at lower temperature
(run 3, 5). Especially, in the use of NaHMDS at -100
°C, the ratio of 21 to 22 was 81:19 and pure 21 was
1
isolated in 57% yield.16 The H NMR spectra of 21 and
22 showed the similar signals and their stereochemistry
could not be fully characterized. However, stereochem-
istry of 21 could be determined by the X-ray crystal-
lographic analysis. On the other hand, syn-selectivity
was observed in the use of KHMDS (run 6-9). The
selectivity was slightly improved in toluene (runs 8, 9).
The best syn-selectivity was obtained in the case of
KHMDS at -90 °C (run 9), in which pure 22 was isolated
in 78% yield.17
The anti-isomer 25 was similarly obtained as a major
product in a moderate yield in the aldol reaction of 9 with
veratraldehyde in THF at -100 °C utilizing LiHMDS or
NaHMDS (Table 3, runs 1 and 2). The anti-selectivity
was in the same level as that of the reaction of 8 with
veratraldehyde. The corresponding syn-isomer 26 was
obtained as a major product under the similar conditions
employing KHMDS (run 3). The selectivity was slightly
improved in toluene (run 4). Although the 1H NMR
spectra of 25 and 26 were similar, the signal of Ha of 26
was observed in the down field by 0.3 ppm compared with
that of 25 probably due to the deshielding effect of the
neighboring carbonyl group as was observed in the case
of 21 (δ 5.44) and 22 (δ 5.67). Therefore the chemical
structures of 25 and 26 seemed to be those as shown in
Scheme 6. They were finally confirmed by conversion of
25 and 26 into the corresponding bislactones 1b and 2a ,
respectively.18
This result indicates that the 3,4-dimethoxyphenyl and
the carboxy groups occupying the cis-positions relative
to each other shield the silyloxy group to retard the
reaction. In order to find out an alternative, efficient
method, we examined the deprotection reaction under the
various conditions and found that treatment of 21 with
NH4F‚HF in the mixed solvent of DMF and N-methyl-
pyrrolidone (NMP) (10:1) for 2 days at room temperature
brought about 23 in 83% yield.19
Although the chemical yields obtained in the above
experiments were adequate, the selectivity in the case
of the anti-isomers 21 and 25 was not necessarily
satisfactory. However, we turned our attention to con-
version of 21, 22, 25, and 26 into the corresponding
bislactones, because 21 related to the diaxial-type isomer
3a being hitherto not synthesized, and 25 could be
obtained more selectively by exchanging the aromatic
aldehydes in the synthesis of 22.
(iii) Con ver sion of th e La cton e 21, 22, 25, a n d 26
in to Bisla cton e 3a , 1a , 1b, a n d 2a . The compounds
22, 25, and 26 were easily converted into the correspond-
ing alcohols 24, 27, and 28, respectively, by treatment
with TBAF-AcOH (1:1) in THF at room temperature.
However, removal of the TBDMS group of 21 proceeded
very slowly under the same reaction conditions to give
only a trace of the desired compound 23 even after 3 days.
The lactonization of 24, 27, and 28 was successfully
achieved by heating in AcOH at 40-50 °C for 30 min to
give the desired bislactones 1a , 1b, and 2a in good yields.
However, the lactonization of 23 did not proceed at all
under the same reaction conditions. Furthermore, the
higher reaction temperature and/or the longer reaction
period induced the isomerization reaction to afford a
significant amount of 1a .20 Thus, the lactonization of 23
was examined under various nonacidic conditions, and
it was found that the lactonization smoothly proceeded
by treatment of 23 with 1-ethyl-3-[3-(dimethylamino)-
propyl]carbodiimide hydrochloride (EDCI) in DMF at
-20-0 °C to afford the diaxial bislactone 3a in 96% yield.
The structure of 3a was unequivocally confirmed on the
basis of X-ray crystallographic analysis. The stere-
ochemistries of structure of 2a were determined by
1
comparison of H NMR with those of diequatorial bis-
lactone analogs reported in the literature.6,21,22 Although
1a and 1b were proved to be the axial-equatorial type
by comparison of reported 1H NMR data,6 the stere-
(16) In order to improve the selectivity, we tried to exchange the
countercation of the enolate of acid anhydride 8 from Li to Mg, Sn or
Zn by addition of the metal salts. But, the lithium enolate of 8 was so
unstable that the enolate of these metals could not be generated.
(17) To the best of our knowledge, it has not been reported that a
potassium countercation of an enolate enhances the stereoselectivity
in its aldol reaction. The high syn-selectivity observed in the use of
KHMDS in the present work would be elucidated by higher stability
of the twist-boat transition structure leading to the syn-isomer than
that of the chair transition structure leading to the anti-isomer.
(18) 1H NMR data of 21, 22, 25, and 26 were summarized in
supporting information.
(19) Seki, M.; Kondo, K.; Kuroda, T.; Yamanaka, T.; Iwasaki, T.
Synlett 1995, 609.
(20) The isomerization of the bislactone under the acidic conditions
was reported by Snieckus et al. See ref 7.
(21) The structure of the diequatorial bislactone 2b (R1 ) R2 ) 3,4-
methylenedioxy) was determined by X-ray crystallographic analyses.
(22) Peterson, J . R.; Peterson, S.; Bakers, J . K.; Roger, R. D. J .
Crystallogr. Spectrosc. Res. 1990, 20, 327.

1314 J . Org. Chem., Vol. 62, No. 5, 1997
Yoshida et al.
toluene (20 mL) and dimethyl maleate (4.9 g, 34 mmol) in
toluene (20 mL) at -70 °C under nitrogen atmosphere. The
mixture was quenched by addition of aqueous AcOH (15%, 30
mL, 76 mmol). The organic layer was separated, and the
aqueous layer was extracted with EtOAc (200 mL). The
combined organic layer was washed with brine (100 mL) and
dried (MgSO4). After evaporation of the solvent, the residue
was dissolved in THF (200 mL), and then AcOH (3.4 mL, 56
mmol) and Bu4NF (1.0 M in THF, 51 mL) were added to the
solution at room temperature. After 30 min, the solution was
washed with water (100 mL), 10% citric acid (100 mL), and
brine (100 mL) and then dried (MgSO4). After evaporation of
the solvent, the residue was purified by silica gel column
chromatography using hexane/EtOAc (1:1) as an eluent to
Sch em e 7
afford 10 as a syrup (8.5 g, 85%): IR (film) 1740, 1678 cm-1
;
1H NMR (200 MHz, CDCl3) δ 3.04 (d, 1H, J ) 7.2 Hz), 3.06 (d,
1H, J ) 7.2 Hz), 3.68, (s, 3H), 3.69 (s, 3H), 4.79 (t, 1H, J ) 7.2
Hz), 6.06 (s, 2H), 6.88 (d, 1H, J ) 8.2 Hz), 7.49 (d, 1H, J ) 1.7
Hz), 7.68 (dd, 1H, J ) 1.7, 8.2 Hz); MS m/z 294 (M+). Anal.
Calcd for C14H14O7: C, 57.14; H, 4.80. Found: 56.75; H, 4.64.
Red u ction of th e Keton e 10. Red u ction w ith L-Selec-
tr id e. To a solution of 10 (1.1 g, 3.7 mmol) in THF (30 mL)
was added dropwise L-Selectride (1 M in THF, 4.1 mL, 4.1
mmol) at -70 °C. After 1 h, the mixture was quenched by
addition of AcOH (0.3 mL) in THF (1 mL) and diluted with
EtOAc (50 mL). The mixture was washed with brine (50 mL),
dried (MgSO4), and concentrated in vacuo. Purification of the
residue on silica gel chromatography using hexane/EtOAc (2:
1) as an eluent afforded d im eth yl 2-(S*)-[r(R*)-h yd r oxy-
3,4-(m eth ylen ed ioxy)p h en yl]su ccin a te (12) (1.0 g, 92%):
mp 97-99 °C; IR (KBr) 3481, 1730, 1708 cm-1; 1H NMR (200
MHz, CDCl3) δ 2.39 (dd, 1H, J ) 5.1, 16.9 Hz), 2.57 (dd, 1H,
J ) 8.7, 16.9 Hz), 3.12 (m, 1H), 3.63 (s, 3H), 3.74 (s, 3H), 4.82
(d, 1H, J ) 7.8 Hz), 5.96 (s, 2H), 6.80 (s, 2H), 6.84 (s, 1H); MS
m/z 296 (M+). Anal. Calcd for C14H16O7: C, 56.76; H, 5.44.
Found: C, 56.70; H, 5.41.
Sch em e 8
Red u ction by P d -Ca ta lyzed Hyd r ogen a tion . A mixture
of 10 (8.4 g, 29 mmol) and 5% Pd on carbon (615 mg) in acetic
acid (40 mL) was stirred under hydrogen atmosphere (3.5
atom) for 5 h at room temperature. After removal of the
catalyst by filtration the filtrate was concentrated in vacuo.
The residue was purified on silica gel chromatography using
hexane/EtOAc (2:1) as an eluent to afford 12 (7.5 g, 88%).
Red u ction w ith Zn (BH4)2. To a suspension of NaBH4 (303
mg, 8.0 mmol) in ether (30 mL) at room temperature under
vigorous stirring was added ZnCl2 (1 M in ether, 4.0 mL, 4.0
mmol). The mixture was vigorously stirred for 5 h. Insoluble
materials were filtered off, and 10 (589 mg, 2.0 mmol) was
added to the filtrate in dry ether (10 mL) at -20 °C. The
mixture was allowed to warm slowly to 0 °C. After 2 h, excess
reagent was decomposed by dropwise addition of AcOH until
the evolution of hydrogen ceased. The solution was washed
with brine (20 mL), dried (MgSO4), and concentrated. The
residue was chromatographed on silica gel using hexane/
EtOAc (2:1) as an eluent to afford tr a n s-3-(m eth oxyca r bon -
yl)-4-[3,4-(m eth ylen edioxy)ph en yl]bu tyr olacton e (13) (415
mg, 79%) and 12 (35 mg, 6%).
ochemistries of 1a and 1b were difficult to distinguish
based on their 1H and 13C NMR spectra. In order to
determine their stereochemistries, 1a and 1b were
converted into 31 and 33, respectively (Schemes 7, 8).
The chemical structure of 31 was confirmed to be methyl
xanthoxylol on the basis of X-ray crystallographic analy-
1
sis.23 On the other hand, H and 13C NMR spectra of
synthesized 33 were identical with those of methyl
pluviatilol (fargesin) reported in the literature.24 Thus,
the stereochemistries of 1a and 1b were unequivocally
confirmed as those shown in Figure 2.
As described above, we have achieved stereocontrolled
syntheses of the four possible stereoisomers of the bis-
lactone furofuran lignans having different aryl groups
including the diaxial type which had never been synthe-
sized. The present methodology should find wide ap-
plication in the synthesis of a variety of bislactone
furofuran lignans.
13: mp 103-104 °C; IR (KBr) 1778, 1734 cm-1 1H NMR
;
(200 MHz, CDCl3) δ 2.93 (m, 2H), 3.32 (m, 1H), 3.77 (s, 3H),
5.55 (d, 1H, J ) 7.5 Hz), 5.59 (s, 2H), 6.81 (s, 3H); MS m/z 264
(M+). Anal. Calcd for C13H12O6: C, 59.09; H, 4.58. Found:
C, 59.17; H, 4.57.
Dim eth yl 2(S*)-[r(R*)-[(ter t-Bu tyld im eth ylsilyl)oxy]-
3,4-(m eth ylen ed ioxy)p h en yl]su ccin a te (15). To a solution
of 12 (30 g, 0.101 mol) in DMF (300 mL) were added imidazole
(16.5 g, 0.24 mol) and TBDMSCl (18.3 g, 0.12 mmol), and the
mixture was stirred for 3 h at room temperature. The mixture
was diluted with EtOAc (1 L), washed with water (1 L) and
brine (1 L), and dried (MgSO4). The solvent was evaporated
in vacuo to dryness. The residue was purified on silica gel
chromatography using hexane/EtOAc (4:1) as an eluent to
Exp er im en ta l Section
Dim et h yl 2-[3,4-(Met h ylen ed ioxy)b en zoyl]su ccin a t e
(10). To LDA (38 mmol) in toluene (200 mL) were added
dropwise successively the cyanohydrin 11 (10 g, 34 mmol) in
afford 15 (38.6 g, 93%) as a syrup: IR (film) 1741 cm-1 1H
;
(23) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(24) Pelter, A.; Ward, R. S.; Rao, E. V.; Sastry, K. V. Tetrahedron
1976, 32, 2783.
NMR (200 MHz, CDCl3) δ -0.21 (s, 3H), 0.01 (s, 3H), 0.84 (s,
9H), 2.23 (dd, 1H, J ) 4.1, 16.7 Hz), 2.53 (dd, 1H, J ) 10.8,
16.7 Hz), 3.14 (m, 1H), 3.59 (s, 3H), 3.71 (s, 3H), 4.76 (d, 1H,
J ) 8.0 Hz), 5.95 (s, 2H), 6.65-6.79 (m, 3H); MS m/z 410 (M+).

Syntheses of Unsymmetrically Substituted Bislactone Lignans
J . Org. Chem., Vol. 62, No. 5, 1997 1315
1
Anal. Calcd for C20H30O7Si: C, 58.51; H, 7.37. Found: C,
58.15; H, 7.17.
(1.12 g, 63%): mp 101 °C; IR (KBr) 1740 cm-1; H NMR (200
MHz, CDCl3) δ -0.17 (s, 3H), 0.02 (s, 3H), 0.88 (s, 9H), 1.40
(s, 9H), 2.59 (d, 1H, J ) 12.9 Hz), 2.95-3.13 (m, 2H), 3.63 (s,
3H), 5.05 (d, 1H, J ) 4.1 Hz), 5.95 (s, 2H), 6.73 (s, 2H), 6.79
(s, 1H); MS m/z 468 (M+). Anal. Calcd for C23H36O6SSi: C,
58.94; H, 7.74. Found: C, 58.87; H, 7.72.
2(S*)-[r(R*)-[(ter t-Bu tyld im eth ylsilyl)oxy]-3,4-(m eth yl-
en ed ioxy)p h en yl]su ccin ic Acid (16). A mixture of 15 (6.7
g, 16 mmol) in methanol (70 mL) and aqueous NaOH (2N, 16
mL, 32 mmol) was stirred for 1 day at room temperature. After
evaporation of MeOH, the residue was dissolved in aqueous
NaOH (2 N, 32 mL, 64 mmol), and the solution was stirred at
50 °C for 2 h. The reaction mixture was poured into a mixture
of water (200 mL) and ether (200 mL). The aqueous layer was
separated, acidified with aqueous HCl (2 N, 50 mL, 100 mmol),
and extracted with EtOAc (400 mL). The organic layer was
washed with brine, dried (MgSO4), and concentrated in vacuo.
The residue was crystallized from ether to give 16 (5.3 g,
2(S*)-[r(R*)-[(ter t-Bu t yld im et h ylsilyl)oxy]-3,4-(m et h -
ylen ed ioxy)ben zyl]-3(S*)-ca r boxy-4(S*)-(3,4-d im eth oxy-
p h en yl)bu tyr ola cton e (22). To a mixture of 8 (331 mg,
0.908 mmol) and veratraldehyde (166 mg, 1.0 mmol) in toluene
(10 mL) was added KHMDS (0.5 M in toluene, 2.0 mL, 1.0
mmol) at -90 °C. The reaction mixture was stirred for 30 min
at the same temperature. The mixture was quenched by
addition of AcOH (0.6 mL, 10 mmol) in toluene (2 mL) and
warmed to room temperature. The mixture was diluted with
EtOAc (30 mL) and washed with water (30 mL), and the
aqueous layer was extracted with EtOAc (30 mL). The
combined organic layer was dried over MgSO4 and evaporated
to dryness in vacuo. The residue was chromatographed on
silica gel using CHCl3/EtOH (20:1) as an eluent to afford a
mixture of 21 and 22 (1:19, 395 mg, 82%). Purification by
silica gel chromatography using CHCl3/EtOH (200:1-50:1) as
an eluent afforded a pure 22 (375 mg, 78%) as a powder: IR
87%): mp 182 °C; IR (KBr) 1713 cm-1 1H NMR (200 MHz,
;
CDCl3) δ -0.16 (s, 3H), 0.36 (s, 3H), 0.85 (s, 9H), 2.29 (dd,
1H, J ) 4.3, 16.8 Hz), 2.46 (dd, 1H, J ) 10.2, 16.8 Hz), 3.14
(m, 1H), 4.90 (d, 1H, J ) 7.2 Hz), 5.94 (s, 2H), 6.72 (s, 2H),
6.82 (s, 1H); MS m/z 382 (M+). Anal. Calcd for C18H26O7Si:
C, 56.52; H, 6.85. Found: C, 56.71; H, 6.83.
2(S*)-[r(S*)[(ter t-Bu tyld im eth ylsilyl)oxy]-3,4-(m eth yl-
en ed ioxy)p h en yl]su ccin ic Acid (20). The acid 20 was
obtained in 90% yield from 19 according to the same procedure
described above and was crystallized from ether: mp 160 °C;
IR (KBr) 3400, 1712 cm-1; 1H NMR (200 MHz, CDCl3) δ -0.17
(s, 3H), -0.01 (s, 3H), 0.87 (s, 9H), 2.32 (dd, H, J ) 2.4, 16.7
Hz), 2.93 (m, 2H), 5.17 (d, 1H, J ) 3.3 Hz), 5.98 (s, 2H), 6.76
(s, 2H), 6.81 (s, 1H); MS m/z 382 (M+). Anal. Calcd for
C18H26O7Si: C, 56.52; H, 6.85. Found: C, 56.38; H, 6.89.
2(S*)-[r(R*)-[(ter t-Bu tyld im eth ylsilyl)oxy]-3,4-(m eth yl-
en ed ioxy)p h en yl]su ccin ic An h yd r id e (8). Suspension of
16 (25 g, 65 mmol) in Ac2O was stirred for 20 min at 60 °C.
After removal of the solvent under reduced pressure, the
residue was crystallized from ether-hexane to afford 8 (22.8
(KBr) 3500, 1780, 1712 cm-1 1H NMR (200 MHz, CDCl3) δ
;
-0.23 (s, 3H), 0.11 (s, 3H), 0.91 (s, 9H), 3.21 (dd, 1H, J ) 3.5,
8.9 Hz), 3.39 (dd, 1H, J ) 8.0, 8.9 Hz), 3.88 (s, 3H), 3.89 (s,
3H), 5.13 (d, 1H, J ) 3.5 Hz), 5.67 (d, 1H, J ) 8.0 Hz), 5.96 (s,
2H), 6.6-7.0 (m, 6H); MS m/z 530 (M+). Anal. Calcd for
C27H34O9Si: C, 61.11; H, 6.46. Found: C, 60.73; H, 6.34.
The compounds 21, 25, and 26 were synthesized in the same
manner, and the experimental details were deposited in the
Supporting Information.
2(S*)-[r(R*)-[(ter t-Bu t yld im et h ylsilyl)oxy]-3,4-(m et h -
ylen ed ioxy)ben zyl]-3(S*)-ca r boxy-4(R*)-(3,4-d im eth oxy-
p h en yl)bu tyr ola cton e (21): mp 221-222 °C; IR (KBr) 3450,
1760, 1720 cm-1; 1H NMR (200 MHz, CDCl3) δ -0.09 (s, 3H),
0.19 (s, 3H), 0.82 (s, 9H), 2.99 (dd, 1H, J ) 5.5, 6.8 Hz), 3.30
(dd, 1H, J ) 6.8, 8.3 Hz), 3.78 (s, 3H), 3.82 (s, 3H), 4.97 (d,
1H, J ) 8.3 Hz), 5.44 (d, 1H, J ) 5.5 Hz), 5.94 (d, 1H, J ) 1.3
Hz), 5.95 (d, 1H, J ) 1.3 Hz), 6.4-6.6 (m, 2H), 6.8 - 7.0 (m,
4H); MS m/z 530 (M+). Anal. Calcd for C27H34O9Si: C, 61.11;
H, 6.46. Found: C, 61.04; H, 6.46.
1
g, 96%): mp 104-105 °C; IR (KBr) 1776 cm-1; H NMR (200
MHz, CDCl3) δ -0.08 (s, 3H), 0.09 (s, 3H), 0.89 (s, 9H), 2.97
(m, 2H), 3.42 (m, 1H), 5.12 (d, 1H, J ) 3.9 Hz), 5.97 (s, 2H),
6.76 (s, 2H), 6.80 (s, 1H); MS m/z 364 (M+). Anal. Calcd for
C18H24O6Si: C, 59.32; H, 6.64. Found: C, 59.20; H, 6.61.
2(S*)-[r(S*)-[(ter t-Bu tyld im eth ylsilyl)oxy]-3,4-(m eth yl-
en ed ioxy)p h en yl]su ccin ic An h yd r id e (9). The anhydride
9 was obtained in 99% yield from 20 according to the same
procedure described above: mp 76 °C; IR (KBr) 1784 cm-1
;
2(S*)-[r(S*)-[(ter t-Bu tyld im eth ylsilyl)oxy]-3,4-(m eth yl-
en ed ioxy)b en zyl]-3(S*)-ca r b oxy-4(R*)-(3,4-d im et h oxy-
p h en yl)bu tyr ola cton e (25): mp 188 °C; IR (KBr) 3420, 1790,
1714 cm-1; 1H NMR (200 MHz, CDCl3) δ -0.35 (s, 3H), -0.08
(s, 3H), 0.80 (s, 9H), 3.37 (dd, 1H, J ) 6.7, 8.2 Hz), 3.78 (dd,
1H, J ) 5.3, 6.7 Hz), 3.87 (s, 6H), 5.06 (d, 1H, J ) 8.2 Hz),
5.51 (d, 1H, J ) 5.3 Hz), 5.97 (d, 1H, J ) 1.4 Hz), 5.99 (d, 1H,
J ) 1.4 Hz), 6.7 - 7.0 (m, 6H); MS m/z 530 (M+). Anal. Calcd
for C27H34O9Si: C, 61.11; H, 6.46. Found: C, 60.97; H, 6.41.
2(S*)-[r(S*)-[(ter t-bu tyld im eth ylsilyl)oxy]-3,4-(m eth yl-
en ed ioxy)b en zyl]-3(S*)-ca r b oxy-4(S*)-(3,4-d im et h oxy-
p h en yl)bu tyr ola cton e (26): mp 168 °C; IR (KBr) 3400, 1780,
1H NMR (200 MHz, CDCl3) δ -0.11 (s, 3H), 0.05 (s, 3H), 0.89
(s, 9H), 2.62 (dd, 1H, J ) 8.5, 17.2 Hz), 3.07-3.23 (m, 2H),
5.35 (s, 1H), 5.98 (s, 2H), 6.79 (s, 3H); MS m/z 364 (M+). Anal.
Calcd for C18H24O6Si: C, 59.32; H, 6.64. Found: C, 59.08; H,
6.60.
Meth yl Hyd r ogen (E)-2-[3,4-(m eth ylen ed ioxy)ben zyli-
d en e]su ccin a te (17). To the solution of 13 (264 mg, 1.0
mmol) in MeOH was added NaOMe (59 mg 1.1 mmol), and
the mixture was stirred for 30 min at 0 °C. After removal of
the solvent under reduced pressure, the residue was crystal-
lized from ether to afford 17 (263 mg, 100%): mp 180 °C; IR
(KBr) 3490, 1706 cm-1; 1H NMR (δ in CDCl3) 3.52 (s, 2H), 3.87
(s, 3H), 6.00 (s, 2H), 6.8-6.9 (m, 3H), 7.78 (s, 1H); MS m/z
264 (M+). Anal. Calcd for C13H12O6: C, 59.09; H, 4.58.
Found: C, 58.88; H, 4.51.
S-ter t-Bu tyl [3(S*)-(Meth oxycar bon yl)-4(S*)-[3,4-(m eth -
ylen ed ioxy)p h en yl]-4-[(ter t-bu tyld im eth ylsilyl)oxy]]bu -
ta n eth ioa te (19). To a solution of trimethylaluminum (2 M
in hexane, 2.3 mL, 4.6 mmol) in CH2Cl2 (15 mL) was added
tert-butylmercaptan (0.52 mL, 4.6 mmol) at 0 °C under a
nitrogen stream. The mixture was allowed to warm to room
temperature and stirred for 20 min. To the mixture was added
13 (1.0 g, 3.8 mmol) in CH2Cl2 (10 mL) at room temperature.
After 1 h, water (10 mL) was added to the mixture, and
insoluble materials were filtered off by a Celite pad. The
filtrate was washed with brine (50 mL), dried (MgSO4), and
concentrated in vacuo. The residue was dissolved in DMF (10
mL), and TBDMSCl (858 mg, 5.7 mmol) and imidazole (775
mg, 11.4 mml) were added to the solution at room temperature.
After 5 h, the reaction mixture was poured into water (100
mL) and extracted with EtOAc (100 mL). The organic layer
was washed with brine (100 mL), dried (MgSO4), and concen-
trated in vacuo. Silica gel column chromatography of the
residue using hexane/EtOAc (4:1) as an eluent afforded 19
1740 cm-1; H NMR (200 MHz, CDCl3) δ -0.18 (s, 3H), 0.03
1
(s, 3H), 0.88 (s, 9H), 3.20 (dd, 1H, J ) 4.2, 8.6 Hz), 3.45 (dd,
1H, J ) 5.2, 8.6 Hz), 3.87 (s, 3H), 3.88 (s, 3H), 5.33 (d, 1H, J
) 4.2 Hz), 5.81 (d, 1H, J ) 5.2 Hz), 5.89 (d, 1H, J ) 1.3 Hz),
5.92 (d, 1H, J ) 1.3 Hz), 6.70 (d, 1H, J ) 7.9 Hz), 6.8-6.9 (m,
5H); MS m/z 530 (M+). Anal. Calcd for C27H34O9Si: C, 61.11;
H, 6.46. Found: C, 60.86; H, 6.38.
(1S *,2S *,5S *,6R *)-2-(3,4-D im e t h o x y p h e n y l)-6-[3,4-
(m eth ylen edioxy)ph en yl]-4,8-dioxo-3,7-dioxabicyclo[3.3.0]-
octa n e (1a ). To a solution of 22 (2.4 g, 4.5 mmol) in THF (50
mL) were added AcOH (0.42 mL, 7.4 mmol) and Bu4NF (1.0
M in THF, 6.8 mL, 6.8 mmol) at room temperature. After
stirring for 1 day, the mixture was diluted with CHCl3 (100
mL), and the solution was washed with 10% citric acid (50
mL) and brine (100 mL). The organic layer was dried over
MgSO4 and evaporated to dryness in vacuo. The residue was
dissolved in AcOH (5 mL), and the reaction mixture was
stirred for 12 h at room temperature and for 30 min at 50 °C.
The mixture was diluted with AcOEt (200 mL) and washed
with brine (100 mL). The organic layer was dried over MgSO4
and concentrated to dryness in vacuo. Silica gel column
chromatography of the residue using hexane/EtOAc (1:1) as
an eluent afforded 1a (1.4 g, 80%): mp 198-199 °C; IR (KBr)

1316 J . Org. Chem., Vol. 62, No. 5, 1997
Yoshida et al.
1792, 1760 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 3.77 (s, 3H),
3.79 (s, 3H), 3.94 (dd, 1H, J ) 3.5, 10.1 Hz), 4.34 (d, 1H, J )
8.6, 10.1 Hz), 5.73 (d, 1H, J ) 3.5 Hz), 5.94 (d, 1H, J ) 8.6
Hz), 6.048 (d, 1H, J ) 0.9 Hz), 6.051 (d, 1H, J ) 0.9 Hz), 6.84
(dd, 1H, J ) 0.5, 8.1 Hz), 6.920 (d, 1H, J ) 1.8 Hz), 6.922 (d,
1H, J ) 8.1 Hz), 6.95 (dd, 1H, J ) 1.8, 8.3 Hz), 6.99 (d, 1H, J
) 8.3 Hz), 7.00 (d, 1H, J ) 0.5 Hz); 13C NMR (100 MHz,
DMSO-d6) δ 45.84, 49.66, 55.53, 55.60, 80.21, 80.30, 101.12,
106.48, 107.92, 109.76, 111.75, 118.56, 119.60, 128.85, 130.89,
147.17, 147.28, 149.01, 149.29, 172.11, 175.05; MS m/z 398
(M+). Anal. Calcd for C21H18O8: C, 63.32; H, 4.55. Found:
C, 63.14; H, 4.53.
60 °C. After refluxing for 1 h, the mixture was quenched by
addition of 10% NaOH (2.4 mL). The insoluble materials were
filtered off by a Celite pad. The filtrate was evaporated to
dryness in vacuo. The residue was purified by silica gel
chromatography using chloroform/EtOH (20:1) as an eluent
to afford 29 (798 mg, 60%): mp 159-160 °C; IR (KBr) 3328
cm-1; 1H NMR (200 MHz, DMSO-d6, D2O exchange) δ 1.69 (m,
1H), 1.96 (m, 1H), 3.5-3.7 (m, 4H), 3.62 (s, 3H), 3.75 (s, 3H),
4.32 (d, 1H, J ) 8.4 Hz), 4.72 (d, 1H, J ) 3.7 Hz), 5.93 (s, 1H),
5.94 (s, 1H), 6.24 (d, 1H, J ) 1.3 Hz), 6.4-6.9 (m, 5H); MS
m/z 406 (M+). Anal. Calcd for C21H26O8: C, 62.06, H, 6.45.
Found: C, 61.87; H, 6.42.
(1S *,2R *,5S *,6S *)-2-(3,4-D im e t h o x y p h e n y l)-6-[3,4-
(m eth ylen edioxy)ph en yl]-4,8-dioxo-3,7-dioxabicyclo[3.3.0]-
octa n e (1b). The bislactone 1b was obtained from 25 in 81%
yield in a same manner described above: mp 195-196 °C; IR
(KBr) 1769 cm-1; 1H NMR NMR (400 MHz, DMSO-d6) δ 3.76
(s, 3H), 3.77 (s, 3H), 3.91 (dd, 1H, J ) 3.5, 10.1 Hz), 4.37 (dd,
1H, J ) 8.6, 10.1 Hz), 5.72 (d, 1H, J ) 3.5 Hz), 5.94 (d, 1H, J
) 8.6 Hz), 6.05 (d, 1H, J ) 1.0 Hz), 6.06 (d, 1H, J ) 1.0 Hz),
6.88 (dd, 1H, J ) 1.9, 8.6 Hz), 6.90 (d, 1H, J ) 1.9 Hz), 6.92-
6.97 (m, 3H), 7.03 (d, 1H, J ) 1.6 Hz); 13C NMR (100 MHz,
DMSO-d6) δ 45.86, 49.78, 55.36, 55.53, 80.09, 80.44, 101.33,
106.33, 108.24, 110.24, 111.32, 118.21, 120.20, 127.29, 132.47,
147.73, 147.82, 148.37, 148.87, 172.01, 175.09; MS m/z 398
(M+). Anal. Calcd for C21H18O8: C, 63.32; H, 4.55. Found:
C, 63.19; H, 4.54.
(1S *,2S *,5S *,6S *)-2-(3,4-D im e t h o x y p h e n y l)-6-[3,4-
(m eth ylen edioxy)ph en yl]-4,8-dioxo-3,7-dioxabicyclo[3.3.0]-
octa n e (2a ). The bislactone 2a was obtained from 26 in 84%
yield in a same manner described above: mp 130 °C; IR (KBr)
1772 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 3.77 (s, 3H), 3.79
(s, 3H), 4.18 (dd, 1H, J ) 2.9, 9.9 Hz), 4.24 (dd, 1H, J ) 2.9,
9.9 Hz), 5.78 (br t, 2H, J ) 2.9 Hz), 6.06 (s, 2H), 6.95 (d, 1H,
J ) 7.9 Hz), 6.94-7.00 (m, 3H), 7.02 (s, 1H), 7.09 (d, 1H, J )
1.3 Hz); 13C NMR (100 MHz, DMSO-d6) δ 47.88, 47.94, 55.54,
55.62, 81.57, 81.63, 101.30, 106.61, 108.14, 109.93, 111.66,
118.76, 120.59, 130.43, 131.95, 147.78, 147.80, 148.99, 149.34,
175.06, 175.09; MS m/z 398 (M+). Anal. Calcd for C21H18O8:
C, 63.32; H, 4.55. Found: C, 63.05; H, 4.51.
(1R*,2R*,3R*,4S*)-2,3-Bis(h ydr oxym eth yl)-1-(3,4-dim eth -
oxyp h en yl)-4-[3,4-(Met h ylen ed ioxy)p h en yl]b u t a n e-1,4-
d iol (32). The tetraol 32 was obtained in 64% yield from 1b
according to the same procedure described above: mp 153-
1
155 °C; IR (KBr) 3314 cm-1; H NMR (200 MHz, DMSO-d6,
D2O exchange) δ 1.78 (m, 1H), 1.92 (m, 1H), 3.5-3.7 (m, 4H),
3.72 (s, 6H), 4.35 (d, 1H, J ) 7.5 Hz), 4.70 (d, 1H, J ) 3.7 Hz),
5.95 (s, 1H), 5.97 (s, 1H), 6.4-6.8 (m, 6H); MS m/z 406 (M+).
Anal. Calcd for C21H26O8: C, 62.06; H, 6.45. Found: C, 61.95;
H, 6.46.
(1R *,2S *,5R *,6R *)-2-(3,4-Dim e t h oxyp h e n yl)-6-[3,4-
(m eth ylen ed ioxy)p h en yl]-3,7-d ioxa bicyclo[3.3.0]octa n e
(31, m eth ylxa n th oxylol). To a solution of 29 (700 mg, 1.7
mmol) in CH2Cl2 (15 mL) containing pyridine (1.4 mL, 17
mmol) was added MsCl (0.4 mL in 5.2 mmol) in CH2Cl2 (2 mL)
at 0 °C. The mixture was stirred at 0 °C for 2 h and at room
temperature for 1 day. The mixture was diluted with CH2-
Cl2, washed with water (50 mL), 10% citric acid (50 mL), and
brine (50 mL), dried (MgSO4), and concentrated. The residue
was purified on silica gel chromatography using hexane/AcOEt
(4:1) as an eluent to afford 31 (325 mg, 51%): mp 115-116
°C; IR (KBr) 1594, 1521, 1243, 1037 cm-1; 1H NMR (400 MHz,
CDCl3) δ 2.90 (m, 1H), 3.28-3.36 (m, 2H), 3.81-3.86 (m, 2H),
3.87 (s, 3H), 3.90 (s, 3H), 4.11 (dd, 1H, J ) 0.9, 9.5 Hz), 4.42
(d, 1H, J ) 7.1 Hz), 4.84 (d, 1H, J ) 5.4 Hz), 5.96 (s, 2H), 6.79
(d, 1H, J ) 7.9 Hz), 6.81 (dd, 1H, J ) 0.8, 1.5 Hz), 6.84 (d, 1H,
J ) 7.9 Hz), 6.87-6.89 (m, 2H), 6.91 (dd, 1H, J ) 1.7, 6.8 Hz);
13C NMR (100 MHz, CDCl3) δ 50.19, 54.55, 55.94, 55.99, 69.68,
70.96, 82.09, 87.63, 100.99, 106.43, 108.16, 109.25, 111.11,
118.52, 118.72, 132.32, 133.68, 146.60, 147.67, 148.80, 149.30;
MS m/z 370 (M+). Anal. Calcd for C21H22O6: C, 68.10; H, 5.99.
Found: C, 67.91; H, 5.97.
2(S*)-[r(R *)-H yd r oxy-3,4-(m e t h yle n e d ioxy)b e n zyl]-
3(S*)-ca r b oxy-4(R*)-(3,4-d im et h oxyp h en yl)b u t yr ola c-
ton e (23). To a solution of 21 (467 mg, 0.88 mmol) in DMF-
NMP (10:1, 10 mL) was added NH4F‚HF (251 mg, 4.4 mmol)
at room temperature. The mixture was stirred for 2 days at
room temperature. The mixture was diluted with EtOAc (40
mL) and washed with water (40 mL). The organic layer was
dried over MgSO4 and concentrated in vacuo. The residue was
crystallized from EtOAc to give 23 (304 mg, 83%): mp 171-
(1R *,2R *,5R *,6S *)-2-(3,4-Dim e t h oxyp h e n yl)-6-[3,4-
(m eth ylen edioxy)ph en yl]-4,8-dioxo-3,7-dioxabicyclo[3.3.0]-
octa n e (33, m eth yl p lu via tilol). 33 was obtained in 58%
yield from 32 according to the same procedure described
1
above: mp 145 °C; IR (KBr) 1591, 1517, 1231, 1028 cm-1; H
1
172 °C; IR (KBr) 3535, 1762, 1705 cm-1; H NMR (200 MHz,
NMR (400 MHz, CDCl3) δ 2.87 (m, 1H), 3.28-3.37 (m, 2H),
3.80-3.91 (m, 2H), 4.11 (dd, 1H, J ) 1.1, 9.5 Hz), 4.43 (d, 1H,
J ) 7.0 Hz), 4.86 (d, 1H, J ) 5.4 Hz), 3.88 (s, 3H), 3.91 (s,
3H), 4.12 (d, 1H, J ) 9.3 Hz), 5.95 (s, 2H), 6.77 (d, 1H, J ) 7.8
Hz), 6.82 (dd, 1H, J ) 1.6, 7.8 Hz), 6.85 (br s, 2H), 6.87 (d, 1H,
J ) 1.6 Hz), 6.92 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ
50.20, 54.64, 55.94, 55.97, 69.76, 71.05, 82.06, 87.69, 101.04,
106.55, 108.16, 109.09, 111.14, 117.76, 119.54, 131.00, 135.23,
147.22, 147.98, 148.10, 148.93; MS m/z 370 (M+). Anal. Calcd
for C21H22O6: C, 68.10; H, 5.99. Found: C, 68.02; H, 5.95.
DMSO-d6, D2O exchange) δ 3.02 (dd, 1H, J ) 5.3, 6.5 Hz), 3.57
(dd, 1H, J ) 6.5, 8.9 Hz), 3.70 (s, 3H), 3.73 (s, 3H), 4.82 (d,
1H, J ) 8.9 Hz), 5.63 (s, 1H, J ) 5.3 Hz), 5.98 (s, 2H), 6.6-7.0
(m, 6H); MS m/z 416 (M+). Anal. Calcd for C21H20O9: C, 60.58;
H, 4.84. Found: C, 60.43; H, 4.76.
(1S *,2R *,5S *,6R *)-2-(3,4-Dim e t h oxyp h e n yl)-6-[3,4-
(m eth ylen edioxy)ph en yl]-4,8-dioxo-3,7-dioxabicyclo[3.3.0]-
octa n e (3a ). To a solution of 23 (58 mg, 0.14 mmol) in DMF
(1.0 mL) was added EDCI (40 mg, 0.21 mmol) at -20 °C. The
mixture was stirred for 1 h at room temperature. The mixture
was diluted with CHCl3 (50 mL), washed with water (50 mL),
dried (MgSO4), and concentrated. The residue was chromato-
graphed on silica gel using CHCl3/EtOH (40:1) as an eluent
to afford 3a (53 mg, 96%): mp 228-230 °C; IR (KBr) 1777
cm-1; 1H NMR (400 MHz, DMSO-d6) δ 3.773 (s, 3H), 3.774 (s,
3H), 4.13 (m, 2H), 5.81 (br t, 2H, J ) 7.8 Hz), 6.05 (d, 1H, J )
0.9 Hz), 6.06 (d, 1H, J ) 0.9 Hz), 6.78-6.85 (m, 3H), 6.88 (d,
1H, J ) 2.0 Hz), 6.93 (d, 1H, J ) 7.9 Hz), 6.97 (d, 1H, J ) 8.3
Hz); 13C NMR (100 MHz, DMSO-d6) δ 46.89, 46.98, 55.37,
55.43, 78.57, 78.80, 101.07, 106.37, 107.88, 109.84, 111.27,
118.14, 119.21, 127.36, 128.99, 147.01, 147.10, 148.26, 148.70,
171.91, 172.06; MS m/z 398 (M+). Anal. Calcd for C21H18O8:
C, 63.32; H, 4.55. Found: C, 63.02; H. 4.44.
Ack n ow led gm en t. We thank Mr. Kimio Okamura
and Mr. Hajime Hiramatsu of our company for X-ray
crystallographic analyses.
Su p p or tin g In for m a tion Ava ila ble: X-ray ORTEP dia-
1
gram of 3a , 21, and 31; H and 13C NMR spectra of 1a , 1b,
2a , 3a , 31, and 33; tables of characterization of 1a , 1b, 2a ,
3a , 21, 22, 25, and 26 by 1H NMR; experimental details of
syntheses of 21, 25, and 26 (19 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
(1S*,2R*,3R*,4R*)-2,3-Bis(h ydr oxym eth yl)-1-(3,4-dim eth -
oxyp h en yl)-4-[3,4-(m et h ylen ed ioxy)p h en yl]b u t a n e-1,4-
d iol (29). To a suspension of LAH (1.2 g, 33 mmol) in THF
(100 mL) was added 1a (1.3 g, 3.3 mmol) in THF (20 mL) at
J O961733Y