Stereoselective syntheses of cis- and trans-isomers of α-hydroxy-α,β-dibenzyl-γ-butyrolactone lignans: New syntheses of (±)-trachelogenin and (±)-guayadequiol

Article abstract of DOI:10.1021/jo9601932

Cis- and trans-isomers of α-hydroxy-α,β-dibenzyl-γ-butyrolactone lignans 1a,d-g and 2a,c,d were stereoselectively synthesized in good yields based on the electrophilic addition to the metal enolate of α-benzyl-γ-butyrolactone derivatives 1l-o and 3 as a key step. This method was applied to the syntheses of (±)-trachelogenin and (±)-guayadequiol, representative examples of the trans- and cis-isomers of α-hydroxy-α,β-dibenzyl-γ-butyrolactone lignan series.

Full text of DOI:10.1021/jo9601932

6922
J . Org. Chem. 1996, 61, 6922-6930
Ster eoselective Syn th eses of Cis- a n d Tr a n s-Isom er s of
r-Hyd r oxy-r,â-d iben zyl-γ-bu tyr ola cton e Lign a n s: New Syn th eses
of (()-Tr a ch elogen in a n d (()-Gu a ya d equ iol
Yasunori Moritani, Chiaki Fukushima,† Tatsuzo Ukita, Toshikazu Miyagishima,†
Hiroshi Ohmizu,* and Tameo Iwasaki*,‡
Lead Optimization Research Laboratory and R & D Planning Division, Tanabe Seiyaku Co., Ltd.,
3-16-89 Kashima, Yodogawa, Osaka 532, J apan
Received J anuary 30, 1996X
Cis- and trans-isomers of R-hydroxy-R,â-dibenzyl-γ-butyrolactone lignans 1a ,d -g and 2a ,c,d were
stereoselectively synthesized in good yields based on the electrophilic addition to the metal enolate
of R-benzyl-γ-butyrolactone derivatives 1l-o and 3 as a key step. This method was applied to the
syntheses of (()-trachelogenin and (()-guayadequiol, representative examples of the trans- and
cis-isomers of R-hydroxy-R,â-dibenzyl-γ-butyrolactone lignan series.
In tr od u ction
Lignans of the R,â-dibenzyl-γ-butyrolactone series1
having a hydroxyl group at the R-position, e.g., trachelo-
genin (1a ),2 wikstromol (1b),3 and guayadequiol (2c),4 are
widely distributed in plants and have attracted consider-
able interest since the discovery of their intriguing
biological activities (Figure 1).2b,5 The stereochemistry
of members within this series of lignans is known to
significantly affect biological activity; as an example, Ca2+
blocking action is observed for trachelogenin, but not for
its stereoisomer, epitrachelogenin.2 Thus, a method is
required for the stereoselective synthesis of both cis- and
trans-isomers of R-hydroxy-R,â-dibenzyl-γ-butyrolactones.
However, no report on the stereoselective synthesis of
this series of lignans is known. In connection with our
efforts in search of new compounds having interesting
biological activities from lignans, we have been interested
in the synthesis of this series of compounds.6 We wish
to report herein a full account of our effort to the first
stereoselective synthesis of cis- and trans-isomers of
R-hydroxy-R,â-dibenzyl-γ-butyrolactone lignans based on
† Lead Optimization Research Laboratory, 2-2-50-Kawagishi, Toda,
Saitama 335, J apan.
‡ R & D Planning Division.
X Abstract published in Advance ACS Abstracts, September 1, 1996.
(1) (a) Rao, C. B. S. Chemistry of lignans; Andhra University Press:
Andhra Pradesh, 1978. (b) Ayres, D. C.; Loike, J . D. Lignans;
Cambridge Univ. Press: Cambridge, 1990. (c) Ward, R. S. Chem. Soc.
Rev. 1982, 11, 75. (d) Ward, R. S. Tetrahedron 1990, 46, 5029. (e)
Yamamura, S. Synth. Org. Chem. J pn. 1985, 43, 583. (f) Ohmizu, H.;
Iwasaki, T. Synth. Org. Chem. J pn. 1995, 53, 593.
F igu r e 1.
(2) (a) Inagaki, I.; Hisada, S.; Nishibe, S. Chem. Pharm. Bull. 1972,
20, 2710. (b) Ichikawa, K.; Kinoshita, T.; Nishibe, S.; Sankawa, U.
Chem. Pharm. Bull. 1986, 34, 3514. (c) Khamlach, L.; Dahl, R.; Brown,
E. Tetrahedron Lett. 1989, 30, 2221.
an electrophilic hydroxylation of the metal enolates of
R-benzyl-γ-butyrolactone derivatives.7
(3) (a) Tandon, S.; Rastogi, R. P. Phytochemistry 1976, 15, 1789. (b)
Torrance, S. J .; Hoffmann, J . J .; Cole, J . R. J . Pharm. Sci. 1979, 68,
664. (c) Belletire, J . L.; Fry, D. F. J . Org. Chem. 1988, 53, 4724 and
references cited within.
(4) Gonza´lez, A.; Este´vez-Reyes, R.; Mato, C.; Este´vez-Braun, A. M.
Phytochemistry 1990, 29, 1981.
(5) (a) Lee, K.-H.; Tagahara, K.; Suzuki, H.; Wu, R.-Y.; Haruna, M.;
Hall, I. H.; Huang, H.-C.; Ito, K.; Ikeda, T.; Lai, J .-S. J . Nat. Prod.
1981, 44, 530. (b) Torrance, S. J .; Hoffmann, J . J .; Cole, J . R. J . Pharm.
Sci. 1979, 68, 664.
(6) (a) Takahashi, M.; Kuroda, T.; Ogiku, T.; Ohmizu, H.; Kondo,
K.; Iwasaki, T. Heterocycles 1993, 36, 1867. (b) Takahashi, M.; Kuroda,
T.; Ogiku, T.; Ohmizu, H.; Kondo, K.; Iwasaki, T. Heterocycles 1993,
36, 1867. (c) Kuroda, T.; Takahashi, M.; Ogiku, T.; Ohmizu, H.;
Nishitani, T.; Kondo, K.; Iwasaki, T. J . Org. Chem. 1994, 59, 7353. (d)
Ogiku, T.; Yoshida, S.; Ohmizu, H.; Iwasaki, T. J . Org. Chem. 1995,
60, 1148. (e) Ogiku, T.; Yoshida, S.; Ohmizu, H.; Iwasaki, T. J . Org.
Chem. 1995, 60, 4585.
Resu lts a n d Discu ssion
Syn th etic Str a tegy a n d MO Ca lcu la tion s of th e
Tr a n sition Str u ctu r es. The most convenient and ef-
ficient method for the synthesis of R-hydroxy-R,â-diben-
zyl-γ-butyrolactones 1a -g and 2a -g would involve the
reaction of the metal enolates of the R,â-dibenzyl-γ-
butyrolactones 1l-o and 2l-o with an oxygen electro-
phile (Scheme 1).
(7) For preliminary communications, see: (a) Moritani, Y.; Ukita,
T.; Nishitani, T.; Seki, M.; Iwasaki, T. Tetrahedron Lett. 1990, 31, 3615.
(b) Moritani, Y.; Fukushima, C.; Ogiku, T.; Ukita, T.; Miyagishima,
T.; Iwasaki, T. Tetrahedron Lett. 1993, 34, 2787.
S0022-3263(96)00193-4 CCC: $12.00 © 1996 American Chemical Society

Syntheses of R-Hydroxy-R,â-dibenzyl-γ-butyrolactone Lignans
J . Org. Chem., Vol. 61, No. 20, 1996 6923
F igu r e 2.
Sch em e 1
Several reports on the stereoselective alkylation of the
metal enolates of γ- and δ-lactones have appeared in the
literature. It is well recognized that an electrophilic
attack on the enolates of â-substituted γ-butyrolactones
is controlled exclusively by the â-substituent, leading to
the trans addition products.8 On the other hand, Koga
and Tomioka reported the reverse diastereofacial dif-
ferentiation in the alkylation of the enolates of R,â-
disubstituted δ-valerolactones; the facial preference is
markedly affected by the exo-allylic substituent, due to
the 1,3-allylic strain, only when the exo-allylic substitu-
ent is much bulkier than the â-substituent.9 We envis-
aged that electrophilic attack on the metal enolates of
1l-o would take place predominantly from the sterically
less hindered upper face in spite of the presence of the
â-substituent, due to the shielding effect of the phenyl
moiety of the R-benzyl group induced by the 1,3-allylic
strain (Figure 2).
F igu r e 3.
Sch em e 2
In order to evaluate our working hypothesis, we carried
out the MO calculations of the transition structures in
the electrophilic addition of methyl iodide to the enolate
of 1l-o by using MNDO program for MOPAC. To
simplify the calculations, -O- Li+ was treated as -O-
and the substituted phenyl groups as nonsubstituted
phenyl ones. The transition structure in the electrophilic
attack from the upper face (A) is estimated to be more
stable by 2.82 kcal/mol than that from the lower face (B)
(Figure 3). This result indicates that the electrophilic
addition to the enolate of 1l-o would give 1d -k in over
98% diastereoexcess (de).10
stable by 3.28 kcal/mol than B (Figure 4); the diastere-
oexcess of the product could be estimated to be over
99%.7b
P r ep a r a tion of th e γ-Bu tyr ola cton es 1l-o, 2l, a n d
3. Our study began with the preparation of γ-butyro-
lactones 1l-o, 2l, and 3. The R,â-dibenzyl-γ-butyrolac-
tones 1l-o and 2l were prepared from the 4-(substituted
benzyl)-γ-butyrolactone 5 obtained by the methods previ-
ously reported (Scheme 3).11 The reaction of the lithium
enolate of 5 with the substituted benzyl bromide afforded
the trans-γ-butyrolactone 1l-o stereospecifically. The
cis-γ-butyrolactone 2l was also synthesized stereospeci-
ficially by treating the lithium enolate of 5a with
substituted benzaldehyde to give the aldol product 6.
Acetylation of 6, followed by treatment with NaH gave
the (E)-R-benzylidene-γ-butyrolactone 7 as a sole product.
Hydrogenation of 7 using 10% Pd on charcoal furnished
2l exclusively.
On the other hand, the above results indicate that the
stereoselective synthesis of the cis-isomer of R-substituted
R,â-dibenzyl-γ-butyrolactone 2a -k by an electrophilic
addition to the enolate of 1l-o is quite difficult. Thus,
an alternative approach as shown in Scheme 2 was
examined by MO calculations in the same manner, and
it was revealed that the transition structure A is more
(8) (a) Hannesian, S.; Murray, P. J . Can. J . Chem. 1986, 64, 2231.
(b) Hannesian, S.; Murray, P. J . J . Org. Chem. 1987, 52, 1170.
(9) (a) Tomioka, K.; Kawasaki, H.; Koga, K. Tetrahedron Lett. 1985,
26, 3027. (b) Tomioka, K.; Yasuda, K.; Kawasaki, H.; Koga, K.
Tetrahedron Lett. 1986, 27, 3247. (c) Tomioka, K.; Kawasaki, H.;
Yasuda, K.; Koga, K. J . Am. Chem. Soc. 1988, 110, 3597.
(10) Similar results were obtained when we calculated the heats of
formation of the transition structure in the electrophilic addition of
methyl iodide to the enolates of dibenzyl lactone using the AM1 or
PM3 program.
(11) (a) Ganeshpure, P. A.; Stevenson, R. J . Chem. Soc., Perkin
Trans. 1 1981, 1681. (b) Schneiders, G. E.; Stevenson, R. J . Chem.
Soc., Perkin Trans. 1 1982, 999. (c) Tomioka, K.; Ishiguro, T.; Koga,
K. Chem. Pharm. Bull. 1985, 33, 4333. (d) Brown, E.; Daugan, A.
Heterocycles 1987, 26, 1169. (e) Lalami, K.; Dahl, R.; Brown, E.
Heterocycles 1988, 27, 1131. (f) Landais, Y.; Robin, J .-P.; Lebrun, A.
Tetrahedron 1991, 47, 3787.

6924 J . Org. Chem., Vol. 61, No. 20, 1996
Moritani et al.
F igu r e 5.
Sch em e 4
F igu r e 4.
Sch em e 3
with L-Selectride occurred stereospecifically to give only
the alcohol 11; the hydride attacks predominantly from
the sterically less hindered site (Figure 5).12 Treatment
of 11 with NaH in DMF afforded 12. The structure of
12a was unambiguously determined by X-ray crystal-
lographic analysis; epimerization at the R-carbon of 12
was found to take place completely during the rearrange-
ment. The primary hydroxyl group of 12 was protected
by MOM group to afford the desired disubstituted R-ben-
zyl-γ-butyrolactone 3.
Syn th esis of tr a n s-r-Hyd r oxy-r,â-d iben zyl-γ-bu -
tyr ola cton es. We first evaluated the diastereoselectiv-
ity in the electrophilic attack on the metal enolate of 1l
and 2l by using methyl iodide (MeI) as an electrophile.
The potassium enolate generated by the reaction of trans-
R,â-dibenzyl-γ-butyrolactone 1l with potassium bis(tri-
On the other hand, the γ-butyrolactone 3, which is
required for the synthesis of cis-R-substituted R,â-diben-
zyl-γ-butyrolactone 2a -k , was prepared starting from
the O-silylated cyanohydrin 8 (Scheme 4). The conjugate
addition of the lithium enolate of 8 to 2(5H)-furanone at
-78 °C followed by trapping the resulting enolate with
3,4-(methylenedioxy)benzyl bromide gave 9. Without
isolation of 9, the resulting mixture was treated with
tetrabutylammonium fluoride to afford the trans-γ-bu-
tyrolactone 10. Reduction of the carbonyl group of 10
(12) Ogiku, T.; Yoshida, S.; Takahashi, M.; Kuroda, T.; Ohmizu, H.;
Iwasaki, T. Tetrahedron Lett. 1992, 33, 4473; 33, 4477.

Syntheses of R-Hydroxy-R,â-dibenzyl-γ-butyrolactone Lignans
J . Org. Chem., Vol. 61, No. 20, 1996 6925
Ta ble 1. Rea ction of th e Meta l En ola tes of 1l-o a n d 2l w ith Electr op h iles
reaction conditions
base
product
additive
(2 equiv)
% yieldb
(1d -k + 2d -k )
selectivity
(1d -k /2d -k )
entry
substrate
(electrophile)
E
1
2
3
4
5
6
7
8
9
10
11
12
13
14f
15f
16f
17f
1l
2l
1l
1l
1l
1l
1l
1l
1l
1l
1l
1l
1l
1l
1m
1n
1o
KHMDS (MeI)
KHMDS (MeI)
KHMDS (D2O)
KHMDS (EtI)
KHMDS (BnBr)
KHMDS (MoOPH)
LDA (MoOPH)
LiHMDS (MoOPH)
NaHMDS (MoOPH)
KHMDS (MoOPH)
KHMDS (MoOPH)
KHMDS (MoOPH)
KHMDS (MoOPH)
KHMDS (MoOPH)
KHMDS (MoOPH)
KHMDS (MoOPH)
KHMDS (MoOPH)
none
none
none
none
none
none
none
none
Me
Me
D
Et
Bn
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
94
91
90
90
90
81
61
42
40
80
81
84
94
94
91
93
94
99/1d
99/1d
94/6c
98/2d
67/33d
61/39d
62/38d
50/50d
53/47d
47/53d
51/49d
55/45d
82/18d
86/14e
83/17e
82/18e
83/17e
none
HMPA
TMEDA
diglyme
18-crown-6
18-crown-6
18-crown-6
18-crown-6
18-crown-6
The reaction was carried out in THF at -78 °C. Isolated yield. c The ratio was determined by 1H NMR. The ratio was determined
a
b
d
by HPLC (CAPCELL PAK C18). e The ratio was determined by isolated yield of each isomers. f The reaction was carried out at -100 °C.
results indicate that an increase in bulkiness of the
electrophile reduces the diastereoselectivity of the reac-
tion.
We next examined the hydroxylation16 of 1l-o prior
to synthesizing (()-trachelogenin and related compounds.
The potassium enolate, generated by treatment of 1l with
KHMDS, was treated with oxodiperoxymolybdenum-
(pyridine)(hexamethylphosphorictriamide) (MoOPH).17 In
this reaction, the trans-isomer 1d was obtained as the
major product, but the diastereoselectivity was rather low
(entry 6 in Table 1). In order to improve the diastereo-
selectivity, we examined the reaction by using a base
other than KHMDS (entries 7-9). However, the dias-
tereoselectivity was not improved in any case, and the
yields were lower. We thought that the presence of the
counter cation in the metal enolate might have slightly
changed the transition structure of the reaction from that
used in the evaluation of our working hypothesis by MO
calculation. This might dramatically alter the expected
diastereoselectivity in the case of a more bulky electro-
phile such as MoOPH. In order to negate the prominent
role of the counter cation on the transition structure, the
reaction was examined in the presence of additives such
as tetramethylethylenediamine (TMEDA), hexameth-
ylphosphorictriamide (HMPA), diglyme, and 18-crown-
6. We first examined the use of HMPA and TMEDA, the
representative nitrogen-containing cation-trapping re-
agents. However, the diastereoselectivity was not im-
proved at all (entries 10, 11). We next examined the
ether type cation trapping reagents, diglyme and 18-
crown-6. Although no improvement in the diastereose-
lectivity and yield was observed in the case of diglyme
(entry 12), the use of 18-crown-6 resulted in a remarkable
improvement in both the diastereoselectivity and yield
(entry 13). Furthermore the diastereoselectivity in-
creased to be 86:14 when the reaction was carried out at
-100 °C (entry 14). Almost the same result was obtained
F igu r e 6.
methylsilyl)amide (KHMDS) in THF at -78 °C was
treated with 3 mol equiv of MeI to afford 1i (Figure 6)13
and 2i in a ratio of >99:1 (94% yield) (entry 1 in Table
1): the ratio determined from HPLC. Furthermore, the
potassium enolate generated from 2l gave almost the
same diastereoselectively (entry 2). These results indi-
cate that the phenyl moiety of the R-benzyl group in the
metal enolate of 1l and 2l is sterically bulky enough to
allow the â-face entry of an electrophile.
In order to evaluate the effect of other electrophiles
on the diastereoselectivity, the enolate was treated with
D2O,14,15 ethyl iodide (EtI), and benzyl bromide (BnBr).
Deuteriation and ethylation of 1l similarly proceeded in
a stereoselective manner to give 1h , 1j as the major
product, respectively (entries 3, 4). However, benzylation
of 1l did not proceed so diastereoselectively, resulting in
a 67:33 ratio of 1k and 2k in 90% yield (entry 5). The
(13) The structure of 1i was unambiguously determined by X-ray
crystallographic analysis and 400 MHz 1H NMR (NOE).
(14) It was suggested in the literature that the deuteriation proceed
by a mechanism different from that of the alkylation. This might be
the reason why the stereoselectivity in the case of deuteriation did
not depend on the order of bulkiness of the electrophiles.15
(15) Deuteriation probably takes place first on oxygen and the
stereochemistry-determining step is the second deuteriation on carbon;
Fleming, I.; Lewis, J . J . J . Chem. Soc., Chem. Commun. 1985, 149.
(16) Brown et al. reported the hydroxylation of the enolate of 1l-o
with molecular hydrogen. However, the diastereoselectivity was not
observed in this reaction, see ref 2c.
(17) Vedejs, E.; Engler, D. A.; Telschow, J . E. J . Org. Chem. 1978,
43, 188.
(18) The NMR spectra of the products (1a , 2c) obtained here were
completely consistent with those of (()-trachelogenin and (()-guay-
adequiol reported in refs 1-3.

6926 J . Org. Chem., Vol. 61, No. 20, 1996
Moritani et al.
3.2
F igu r e 8.
F igu r e 9.
F igu r e 7.
Sch em e 5
Ta ble 2. Rea ction of th e Meta l En ola tes of 3a -c w ith
Electr op h iles
Sch em e 6
riation and ethylation of 3a using D2O and EtI, respec-
tively, as electrophiles was found to proceed smoothly
with a high level of diastereoselectivity to afford 4d , 4f
as the sole product (entries 2, 3). Furthermore, hydroxy-
lation of 3 also proceeded with high diastereoselectivity
to give 4a -c20 exclusively (Figure 8, entries 4-6). The
results are summarized in Table 2.
% yieldb selectivity
entry substrate electrophile
E
(4+4′)
(4/4′)
1
2
3
4
5
6
3a
3a
3a
3a
3b
3c
MeI
D2O
EtI
MoOPH
MoOPH
MoOPH
Me
D
Et
OH
OH
OH
87
92
89
89
83
81
>99/1d
>99/1c
>99/1d
>99/1d
>99/1d
>99/1d
We next investigated the conversion of 4a -f into the
desired cis-dibenzyl lactones 2a , 2c, 2d , 2h -j (Scheme
6). In order to cleave the lactone ether bond, hydro-
genolysis of 4a was examined in several solvents using
10% Pd on charcoal as a catalyst. In THF or THF-
MeOH, the reaction proceeded very sluggishly; even after
24 h at room temperature, little product (13a ) was
obtained. However, the reaction proceeded smoothly to
13a in AcOH containing a catalytic amount of concd H2-
SO4. Without isolation of 13a , the mixture was treated
under aqueous acidic conditions to afford the desired
product 2d in 85% yield. Other compounds 2a , 2c, 2h ,
2i (Figure 9)21 and 2j were also obtained in moderate to
good yield by the same procedure described above.
This method was applied to the synthesis of (()-
guayadequiol (2c), a representative example of the
naturally occurring lignans. Hydroxylation of the metal
enolate of 3b with MoOPH proceeded in a highly dias-
tereoselective manner to afford the trans-product 4b
(Figure 8, entry 6 in Table 2).22 This was nicely trans-
a
The reaction was carried out in THF at -78 °C using KHMDS
as a base. Isolated yield. c The ratio was determined by 1H NMR
b
d
after transformation into 2. The ratio was determined by HPLC
(CAPCELL PAK C18) after transformation into 2.
in the case of 1n , the precursor of (()-trachelogenin (1f)
(entry 16). Hydrogenolysis of 1f afforded (()-trachelo-
genin (1a )18 in 96% yield. (Scheme 5).
Syn th esis of cis-r-Hyd r oxy-r,â-d iben zyl-γ-bu ty-
r ola cton es. In order to further evaluate our working
hypotheses (3 to 4 in Scheme 2), we similarly examined
electrophilic additions to the metal enolates of γ-butyro-
lactones 3 by using D2O, MeI and EtI as electrophiles.
The potassium enolate generated by reaction of 3a with
KHMDS in THF at -78 °C was treated with MeI to
furnish 4e (Figure 7)19 and its stereoisomer 4′e in 87%
yield, in a ratio of >99:1 by the HPLC analysis (entry 1
in Table 2). We next attempted to introduce a variety of
electrophiles into the metal enolate of 3 prior to synthe-
sizing (()-guayadequiol 2c and its derivatives. Deute-
(20) The structure of 4a was determined by 200 MHz 1H NMR.
(21) The structure of 2i was unambiguously determined by X-ray
crystallographic analysis and 400 MHz 1H NMR (NOE).
(19) The structure of 4e was determined by 400 MHz 1H NMR.
(22) The structure of 4b was determined by 200 MHz 1H NMR.

Syntheses of R-Hydroxy-R,â-dibenzyl-γ-butyrolactone Lignans
J . Org. Chem., Vol. 61, No. 20, 1996 6927
formed into (()-guayadequiol (2c)18 using the same
using hexane/AcOEt (1:1) as an eluent to afford 5a (58.2 g,
90%) as a colorless oil.
procedure described above.
4-(3,4-Dim eth oxyben zyl)-γ-bu tyr olacton e (5a): 47% yield
from veratraldehyde; IR (film) 1778 cm-1 1H NMR (δ in
;
Con clu sion
CDCl3); 2.29 (dd, 1H, J ) 6.5, 17.4 Hz), 2.61 (dd, 1H, J ) 7.8,
17.4 Hz), 2.65-2.98 (m, 3H), 3.87 (s, 3H), 3.88 (s, 3H), 4.04
(dd, 1H, J ) 5.6, 9.0 Hz), 4.34 (dd, 1H, J ) 6.6, 9.1 Hz), 6.67
(s, 1H), 6.69 (dd, 1H, J ) 1.9, 7.9 Hz), 6.82 (d, 1H, J ) 7.9
Hz); MS m/z (relative intensity, %): 236 (M+, 57), 151 (100).
Anal. Calcd for C13H16O4: C, 68.10; H, 5.99. Found: C, 67.92;
H, 5.98.
We present here a highly stereoselective electrophilic
addition reaction to the metal enolate of the â-substituted
R-benzyl-γ-butyrolactone derivatives 1l-o and 3. The
stereoselectivity observed in this reaction presumably
originates from the conformational rigidity of the metal
enolate of 1l-o and 3 induced by 1,3-allylic strain. Using
this reaction, the first stereoselective synthesis of both
cis- and trans-isomers of R-substituted R,â-dibenzyl-γ-
butyrolactones was accomplished. This method should
find wide application in the stereoselective synthesis of
a variety of cis- and trans-isomers of R-substituted R,â-
dibenzyl-γ-butyrolactone lignans having intriguing bio-
logical activities.
(3R *,4R *)-3-[3,4-(Me t h y le n e d io x y )b e n zy l]-4-(3,4-
d im eth oxyben zyl)-γ-bu tyr ola cton e (1l). LDA (60.4 mmol)
was prepared in 60 mL of THF by the normal method.6d To
the solution cooled to -78 °C was added dropwise 5a (11.9 g,
50.3 mmol) in THF (30 mL) while maintaining the same
temperature. After 20 min, 3,4-(methylenedioxy)benzyl bro-
mide (10.8 g, 50.3 mmol) in THF (30 mL) was added to the
mixture, which was stirred for an additional 3 h at -78 °C.
The mixture was quenched with saturated aqueous am-
monium chloride, the organic layer separated, and the aqueous
layer extracted with AcOEt. The combined organic layers were
washed with water and brine and dried over MgSO4. Evapo-
ration of the solvent provided the crude product as a solid,
which was collected by filtration and washed with Et2O to
afford 1l (16.0 g, 86%): mp 107-8 °C (AcOEt-hexane); IR
Exp er im en ta l Section
Gen er a l Con sid er a tion s. All melting points are uncor-
rected. HPLC analyses were performed with SHISEIDO
CAPCELLPAC C18 (SG 120, S-5 µm, 4.6 × 150 mm) and a
flow rate of 0.5 mL/min.
(KBr) 1767 cm-1 1H NMR (δ in CDCl3) 2.37-2.73 (m, 4H),
;
2.85 (dd, 1H, J ) 6.4, 14.0 Hz), 2.97 (dd, 1H, J ) 4.9, 13.9
Hz), 3.83 (s, 3H), 3.86 (s, 3H), 3.81-3.98 (m, 1H), 4.15 (dd,
1H, J ) 6.8, 9.3 Hz), 5.90-5.99 (m, 2H), 6.48 (d, 1H, J ) 1.9
Hz), 6.52-6.61 (m, 1H), 6.57-6.67 (br s, 2H), 6.69-6.83 (m,
2H); MS m/z (relative intensity, %): 370 (M+, 50), 151 (73),
135 (100). Anal. Calcd for C21H22O6: C, 68.10; H, 5.99.
Found: C, 67.92; H, 5.98.
Com p u ta tion a l Meth od s. Semiempirical molecular or-
bital calculations were carried out using MNDO Hamiltonian
implemented in MOPAC 5.0.23 Conformational analyses were
previously done using the command SEARCH in SYBYL24 with
TRIPOS force field. All structures were refined using the
keyword PRESCISE. Transition structures were calculated
by using bond lengths of I-C(Me) and C(Me)-CR as reaction
coordinates, using product structures as starting structures
in calculations for convenience. The structures were further
optimized with the keyword NLLSQ, and then vibrational
analyses were done with the keyword FORCE, to verify the
transition structures.
Syn th esis of cis-r,â-Diben zyl-γ-bu tyr ola cton es (2l).
Reaction of LDA (36.0 mmol) in 50 mL of THF and 5a (7.08 g,
30 mmol) in THF (20 mL) was carried out as described for 1l.
After 20 min, further reaction with 3,4-(methylenedioxy)-
benzaldehyde (4.50 g, 30 mmol) in THF (10 mL) for 1 h at
-78 °C followed by workup as described for 1l provided crude
6 as an oil. Without isolation, 6 was treated with acetic
anhydride (3.68 mL, 39.0 mmol), triethylamine (5.44 mL, 39.0
mmol), and (dimethylamino)pyridine (0.37 g, 3 mmol) in THF
(100 mL) at room temperature for 5 h. The reaction mixture
was poured into water, and the aqueous layer was extracted
with AcOEt. The combined organic layers were washed with
water and brine and dried over MgSO4. Evaporation of the
solvent provided the acetylated product after purification by
silica gel column chromatography using CHCl3/AcOEt (20:1)
as an eluent. The acetate was dissolved in THF (100 mL),
and sodium hydride (2.40 g, 60 mmol) was added portionwise
to the mixture at 0 °C. The mixture was stirred at room
temperature for 12 h, quenched with water, and acidified to
pH ) 1-2 with 2 N HCl. The aqueous layer was extracted
with AcOEt, and the combined organic layers were washed
with water and brine and dried over MgSO4. Evaporation of
the solvent provided the exo-olefin 7 as a solid, which was
collected by filtration and washed with Et2O (10.1 g, 92%). A
sample of 7 (8.88 g, 24.1 mmol) was dissolved in a mixture of
THF (80 mL) and MeOH (40 mL), and 10% Pd/C (500 mg)
catalyst was added. The mixture was stirred under H2 (1 atm,
rt) for 4 h followed by filtration and evaporation to give cis-
dibenzyl lactone 2l (8.31 g, 93%) as the sole product.
Syn t h esis of â-Ben zyl-γ-b u t yr ola ct on es 5. Typ ica l
P r oced u r e. To a solution of t-BuOK (67.6 g, 0.602 mol) in
t-BuOH (600 mL) were added veratraldehyde (100 g, 0.602
mol) and dimethyl succinate (80.9 mL, 0.602 mol), keeping the
temperature below 40 °C. After stirring for 30 min, the
mixture was poured into water and extracted with i-Pr2O. The
aqueous layer was acidified with concd HCl and extracted with
AcOEt. The organic layer was washed with water and brine
and dried over MgSO4. Evaporation of the solvent provided
the veratrylidene half ester as a yellowish solid, which was
collected by filtration and washed with Et2O (94.0 g, 56%). The
yellowish solid (75.0 g, 0.267 mol) was suspended in MeOH
(800 mL) and stirred under nitrogen. 10% Pd on charcoal (4.0
g) was added, and the mixture was stirred under hydrogen at
atmospheric pressure for 6 h. Filtration and evaporation gave
the veratryl half ester as a white solid, which was collected
by filtration and washed with Et2O (70.0 g, 93%). The
potassium salt was prepared by addition of ethanolic t-BuOK
(27.8 g, 0.248 mol in 600 mL of EtOH) to a suspension of the
veratryl half ester in EtOH (600 mL) until basic to phenol-
phthalein. Powdered anhydrous CaCl2 (100 g, 0.90 mol) was
dissolved in anhydrous EtOH (800 mL) and cooled to -10 °C.
To this was added a solution of NaBH4 (70.0 g, 1.85 mol) in
EtOH (1800 mL) over 1 h at -10 °C, the potassium salt in
EtOH was added to the borohydride solution over 1 h at -78
°C, and the mixture was stirred for 12 h at room temperature.
The mixture was concentrated, and the residue was dissolved
in water and CHCl3, acidified by concd HCl to pH ) 1-2, and
refluxed for 30 min. The organic layer of the cooled reaction
mixture was separated, washed with water and brine, and
dried over MgSO4. Evaporation of the solvent left a yellowish
oil that was purified by silica gel column chromatography
(3E )-[3,4-(M e t h y le n e d i o x y )b e n z y li d e n e ]-4-(3,4-
d im eth oxyben zyl)-γ-bu tyr ola cton e (7): mp 95-6 °C (AcO-
1
Et-hexane); IR (KBr) 1738 cm-1; H NMR (δ in CDCl3) 2.63
(dd, 1H, J ) 9.9, 14.2 Hz), 3.02 (dd, 1H, J ) 4.4, 14.2 Hz),
3.70-3.91 (m, 1H), 3.86 (s, 3H), 3.88 (s, 3H), 4.20-4.36 (m,
2H), 6.04 (s, 2H), 6.66-6.92 (m, 4H), 7.02-7.14 (m, 2H), 7.51
(d, 1H, J ) 1.8 Hz); MS m/z (relative intensity, %): 368 (M+,
25), 217 (8), 151 (100). Anal. Calcd for C21H20O6: C, 68.47;
H, 5.47. Found: C, 68.44; H, 5.29.
(3S *,4R *)-3-[3,4-(Me t h y le n e d i o x y )b e n z y l]-4-(3,4-
d im eth oxyben zyl)-γ-bu tyr ola cton e (21): mp 103-4 °C
(23) MOPAC Ver. 5, J . J . P. Stewart, QCPE No. 455; Revised as
Ver. 5.01 by T. Hirano, for UNIX machines, J CPE Newletter 1989,
1(2), 36.
1
(AcOEt-hexane); IR (KBr) 1771 cm-1; H NMR (δ in CDCl3)
(24) TRIPOS, Inc., 1699 S. Hanley Road, St. Louis, MO 63144-2913.
2.32 (dd, 1H, J ) 12.3, 13.3 Hz), 2.59-2.78 (m, 1H), 2.76 (dd,

6928 J . Org. Chem., Vol. 61, No. 20, 1996
Moritani et al.
1H, J ) 10.3, 14.6 Hz), 2.93 (dd, 1H, J ) 9.8, 13.6 Hz), 2.98-
3.12 (m, 1H), 3.23 (dd, 1H, J ) 4.7, 14.5 Hz), 3.84 (s, 3H), 3.85
(s, 6H), 3.96-4.13 (m, 2H), 5.96 (s, 2H), 6.53 (d, 1H, J ) 1.9
Hz), 6.61 (dd, 1H, J ) 1.9, 8.1 Hz), 6.70-6.85 (m, 4H); MS
m/z (relative intensity, %): 370 (M+, 60), 151 (59), 135 (100).
Anal. Calcd for C21H22O6: C, 68.10; H, 5.99. Found: C, 68.04;
H, 5.79.
2.50-2.82 (m, 2H), 2.70 (d, 1H, J ) 14.1 Hz), 2.86-2.98 (m,
1H), 2.96 (d, 1H, J ) 11.9 Hz), 3.04 (d, 1H, J ) 13.8 Hz), 3.23
(d, 1H, J ) 14.0 Hz), 3.50 (dd, 1H, J ) 8.8, 10.6 Hz), 3.74-
3.89 (m, 1H), 3.84 (s, 6H), 5.92 (s, 2H), 6.48-6.81 (m, 6H),
7.18-7.43 (m, 5H); MS m/z (relative intensity, %): 460 (M+,
17), 151 (30), 135 (100). Anal. Calcd for C28H28O6: C, 73.03;
H, 6.13. Found: C, 72.98; H, 6.32.
Deu ter ia tion of th e Meta l En ola te of 1l. A solution of
1l (430 mg, 1.16 mmol) in 5 mL of THF was added to the
solution of KHMDS (488 mg, 2.32 mmol) in 8 mL of THF at
-78 °C, and the mixture was stirred for 30 min at the same
temperature. To the mixture was added dropwise D2O (1.0
mL, large excess), and it was stirred for 1 h. The organic layer
was separated and dried over MgSO4. Evaporation of the
solvent provided a mixture of 1h and 2h , which was separated
by silica gel column chromatography using hexane/CHCl3/
AcOEt (10:10:1) as the eluent; the ratio of isomers was
(3S*,4R*)-3-Ben zyl-3-[3,4-(m et h ylen ed ioxy)b en zyl]-4-
(3,4-d im eth oxyben zyl)-γ-bu tyr ola cton e (2k ): mp 122-3 °C
1
(AcOEt-hexane); IR (KBr) 1761 cm-1; H NMR (δ in CDCl3)
2.43-2.78 (m, 2H), 2.74 (d, 1H, J ) 13.8 Hz), 2.82-3.08 (m,
3H), 3.33 (d, 1H, J ) 13.8 Hz), 3.60 (dd, 1H, J ) 8.6, 10.6 Hz),
3.74-3.89 (m, 1H), 3.81 (s, 3H), 3.84 (s, 3H), 5.97 (s, 2H), 6.44-
6.83 (m, 6H), 7.13-7.42 (m, 5H); MS m/z (relative intensity,
%); 460 (M+, 29), 338 (43), 151 (45), 135 (100). Anal. Calcd
for C28H28O6: C, 73.03; H, 6.13. Found: C, 73.14; H, 6.22.
Hyd r oxyla tion of th e Meta l En ola te of 1l-o. Gen er a l
P r oced u r e. A solution of 1l-o (1.00 mmol) in 8 mL of THF
was added to a solution of the base (2.00 mmol) in 8 mL of
THF at -78 °C and additive (2.00 mmol) in 3 mL of THF if it
is necessary. The mixture was stirred for 30 min at the same
temperature. To the mixture was added MoOPH (533 mg, 1.50
mmol) in one portion, and it was stirred for 1-2 h. The
mixture was quenched by addition of saturated aqueous
sodium sulfate (5 mL). The organic layer was separated, and
the aqueous layer was extracted with AcOEt. The combined
organic layers were washed with 2 N HCl, water, and brine
1
determined by H NMR analysis.
(3R*,4R*)-3-Deu ter io-3-[3,4-(m eth ylen ed ioxy)ben zyl]-
4-(3,4-d im eth oxyben zyl)-γ-bu tyr ola cton e (1h ): mp 98-9
°C (AcOEt-hexane); IR (KBr) 1767 cm-1; 1H NMR (δ in CDCl3)
2.39-2.68 (m, 3H), 2.74 (d, 1H, J ) 14.2 Hz), 2.97 (d, 1H, J )
14.1 Hz), 3.83 (s, 3H), 3.86 (s, 3H), 3.82-3.93 (m, 1H), 4.15
(dd, 1H, J ) 7.1, 9.5 Hz), 5.91-5.99 (m, 2H), 6.48 (d, 1H, J )
1.9 Hz), 6.51-6.59 (m, 1H), 6.60 (s, 2H), 6.68-6.84 (m, 2H);
MS m/z (relative intensity, %): 371 (M+, 44), 151 (73), 135
(100).
(3R*,4S*)-3-Deu ter io-3-[3,4-(m eth ylen ed ioxy)ben zyl]-
4-(3,4-d im eth oxyben zyl)-γ-bu tyr ola cton e (2h ): mp 102-3
°C (AcOEt-hexane); IR (KBr) 1774 cm-1; 1H NMR (δ in CDCl3)
2.32 (dd, 1H, J ) 12.3, 13.3 Hz), 2.59-3.12 (m, 3H), 3.22 (d,
1H, J ) 14.9 Hz), 3.84 (s, 3H), 3.85 (s, 3H), 3.96-4.12 (m, 2H),
5.96 (s, 2H), 6.53 (d, 1H, J ) 1.9 Hz), 6.61 (dd, 1H, J ) 1.9,
8.1 Hz), 6.71-6.87 (m, 4H); MS m/z (relative intensity, %); 371
(M+, 89), 151 (69), 135 (100).
and dried over MgSO4
. Evaporation of the solvent provided a
crude mixture, which was purified by silica gel column
chromatography using hexane/CHCl3/AcOEt (5:5:3) as the
eluent to afford 1d -g and 2d -g as colorless crystalline solids.
The yield and the ratio of each isomer are shown in Table 1.
(3S*,4S*)-3-Hyd r oxy-3-[3,4-(m eth ylen ed ioxy)ben zyl]-4-
(3,4-d im eth oxyben zyl)-γ-bu tyr ola cton e (1d ): mp 153-4 °C
(AcOEt); IR (KBr) 3426, 1754 cm-1 1H NMR (δ in CDCl3)
;
Alk yla tion of th e Meta l En ola te of 1l-o, 2l. Typ ica l
P r oced u r e. The potassium enolate of 1l (370 mg, 1.00 mmol)
was prepared from KHMDS (420 mg, 2.00 mmol) as described
above for 1h and 2h . To the mixture was added dropwise MeI
(0.187 mL, 3.00 mmol) in 8 mL of THF. After 2 h, the mixture
was quenched by addition of saturated aqueous ammonium
chloride, the organic layer was separated and the aqueous
layer was extracted with AcOEt. The combined organic layers
were washed with saturated aqueous sodium thiosulfate,
water, and brine and dried over MgSO4. Evaporation of the
solvent provided 1i as the sole product, which was purified by
silica gel column chromatography using hexane/CHCl3/AcOEt
(10:10:1) as the eluent. The diastereoselectivity was deter-
mined by HPLC with 45:55 CH3CN-H2O as the mobile phase.
(3R*,4R*)-3-Meth yl-3-[3,4-(m eth ylen ed ioxy)ben zyl]-4-
(3,4-d im eth oxyben zyl)-γ-bu tyr ola cton e (1i): mp 96-7 °C
(AcOEt-hexane); IR (KBr) 1777, 1517, cm-1; 400 MHz 1H
NMR (δ in CDCl3), 1.25 (m, 3H), 2.36 (dd, 1H, J ) 11.0, 13.4
Hz), 2.48-2.68 (m, 1H), 2.64 (d, 1H, J ) 14.0 Hz), 2.69 (dd,
1H, J ) 4.0, 13.4 Hz), 3.15 (d, 1H, J ) 14.0 Hz), 3.83 (dd, 1H,
J ) 9.1, 10.2 Hz), 3.85 (s, 3H), 3.86 (s, 3H), 3.98 (dd, 1H, J )
7.8, 9.1 Hz), 5.93 (s, 2H), 6.55 (d, 1H, J ) 2.2 Hz), 6.60 (dd,
1H, J ) 2.1, 8.3 Hz), 6.64 (dd, 1H, J ) 2.1, 8.3 Hz), 6.70 (d,
1H, J ) 1.6 Hz), 6.74 (d, 1H, J ) 7.8 Hz), 6.77 (d, 1H, J ) 8.3
Hz); MS m/z (relative intensity, %); 384 (M+, 27), 151 (17), 135
(100). Anal. Calcd for C22H24O6: C, 68.74; H, 6.29. Found:
C, 68.56; H, 6.12.
2.41-2.64 (m, 3H), 2.91 (d, 1H, J ) 13.8 Hz), 3.07 (d, 1H, J )
13.8 Hz), 2.90-3.02 (m, 1H), 3.86 (s, 6H), 3.95-4.13 (m, 2H),
5.94 (s, 2H), 6.57-6.85 (m, 6H); MS m/z (relative intensity,
%): 386 (M+, 17), 151 (13), 135 (100), 77 (6). Anal. Calcd for
C21H22O7: C, 65.28; H, 5.74. Found: C, 65.19; H, 5.63.
(3R*,4S*)-3-Hyd r oxy-3-[3,4-(m et h ylen ed ioxy)b en zyl]-
4-(3,4-d im eth oxyben zyl)-γ-bu tyr ola cton e (2d ): mp 140-1
1
°C (AcOEt); IR (KBr) 3520, 1783 cm-1; H NMR (δ in CDCl3)
2.64 (dd, 1H, J ) 11.3, 13.2 Hz), 2.73 (s, 1H), 2.82-3.06 (m,
3H), 3.13 (dd, 1H, J ) 4.0, 13.3 Hz), 3.87 (s, 3H), 3.88 (s, 3H),
3.93 (dd, 1H, J ) 10.1, 10.1 Hz), 4.20 (dd, 1H, J ) 7.7, 9.1
Hz), 5.96 (s, 2H), 6.62-6.87 (m, 6H); MS m/z (relative intensity,
%): 386 (M+, 13), 151 (9), 135 (100), 77 (5). Anal. Calcd for
C21H22O7: C, 65.28; H, 5.74. Found: C, 65.06: H, 5.54.
(()-Tr a ch elogen in (1a ). Trans-lactone 1f (0.60 g, 1.26
mmol) was dissolved in a mixture of THF (10 mL) and MeOH
(10 mL), and 10% Pd/C (100 mg) was added. The mixture was
stirred under a hydrogen atmosphere at 25 °C for 6 h.
Filtration of the catalyst and evaporation of the solvent left
468 mg (96% yield) of a crude solid. Recrystallization from
MeOH furnished pure 1a as prisms: mp 138-9 °C (MeOH)
[lit.2a mp 130-140 °C; lit.2c (-)-trachelogenin: mp 139.3-140.5
°C (CH2Cl2-ether)]; IR (KBr) 3455, 1752 cm-1; 1H NMR (δ in
CDCl3) 2.44-2.63 (m, 2H), 2.61 (s, 1H), 2.88-3.07 (m, 1H),
2.93 (d, 1H, J ) 13.8 Hz), 3.11 (d, 1H, J ) 13.7 Hz), 3.848 (s,
3H), 3.853 (s, 3H), 3.86 (s, 3H), 3.93-4.13 (m, 2H), 5.59 (s, 1H),
6.58-6.90 (m, 6H); MS m/z (relative intensity, %): 388 (M+,
12), 151 (14), 137 (100). Anal. Calcd for C21H24O7: C, 64:94;
H, 6.23. Found: C, 64.88: H, 6.39.
Ethylation and benzylation of 1l were conducted in the same
manner described above.
(3R*,4R*)-3-E t h yl-3-[3,4-(m et h ylen ed ioxy)b en zyl]-4-
(3,4-d im eth oxyben zyl)-γ-bu tyr ola cton e (1j): mp 138-9 °C
Syn th esis of Cya n oh yd r in s (8). Compounds 8a and 8b
were prepared from the substituted benzaldehyde by the
reported method.6e
1
(AcOEt); IR (KBr) 1761 cm-1; H NMR (δ in CDCl3), 1.13 (t,
3H, J ) 7.4), 1.58-1.91 (m, 2H), 2.31-2.77 (m, 3H), 2.60 (d,
1H, J ) 14.1 Hz), 3.24 (d, 1H, J ) 14.0 Hz), 3.72-3.99 (m,
2H), 3.85 (s, 6H), 5.93 (s, 2H), 6.48-6.82 (m, 6H); MS m/z
(relative intensity, %): 400 (M+, 64), 207 (18), 181 (59), 135
(100). Anal. Calcd for C23H26O6: C, 69.33; H, 6.58. Found:
C, 69.20; H, 6.32.
(3R *,4R *)-3-[3,4-(Me t h y le n e d io x y )b e n zy l]-4-(3,4-
dim eth oxyben zoyl)-γ-bu tyr olacton e (10a). LDA (0.35 mol)
in THF (400 mL) was prepared by the normal method and
cooled to -78 °C. To the solution was added dropwise 8a (90.0
g, 0.290 mol) in THF (200 mL) under vigorous stirring, followed
by successive addition of 2(5H)-furanone (20.7 mL, 0.290 mol)
in THF (200 mL) and 3,4-(methylenedioxy)benzyl bromide
(63.0 g, 0.290 mol) in THF (100 mL) at the same temperature.
After 3 h, the mixture was quenched by addition of saturated
(3R*,4R*)-3-Ben zyl-3-[3,4-(m eth ylen ed ioxy)ben zyl]-4-
(3,4-d im eth oxyben zyl)-γ-bu tyr ola cton e (1k ): mp 101-2 °C
1
(AcOEt-hexane); IR (KBr) 1762 cm-1; H NMR (δ in CDCl3)

Syntheses of R-Hydroxy-R,â-dibenzyl-γ-butyrolactone Lignans
J . Org. Chem., Vol. 61, No. 20, 1996 6929
aqueous ammonium chloride. The organic layer was sepa-
rated, and the aqueous layer was extracted with AcOEt. The
combined organic layers were washed with water and brine
and dried over MgSO4. Evaporation of the solvent provided
the crude product (9a ) as an oil. To the solution of the oily
product in CH2Cl2 (1500 mL) was added 1 M Bu4NF in THF
(293 mL, 0.290 mol) at 0 °C. After 30 min, the solution was
washed with water, 10% citric acid, and brine and dried over
MgSO4. Evaporation of the solvent afforded a crude product,
which was crystallized from MeOH to give 10a (80.8 g, 72%
from 8a ) as the sole product: mp 140-1 °C (AcOEt-acetone):
IR (KBr) 1772, 1665 cm-1; 1H NMR (δ in CDCl3) 2.93 (dd, 1H,
J ) 7.2, 14.2 Hz), 3.06 (dd, 1H, J ) 5.5, 14.2 Hz), 3.42-3.63
(m, 1H), 3.17 (dd, 1H, J ) 3.8, 13.2 Hz), 3.92 (s, 3H), 3.96 (s,
3H), 4.01-4.23 (m, 2H), 4.32-4.51 (m, 1H), 5.85 (d, 1H, J )
1.3 Hz), 5.88 (d, 1H, J ) 1.4 Hz), 6.49-6.68 (m, 3H), 6.84 (d,
1H, J ) 8.4 Hz), 7.23-7.41 (m, 2H); MS m/z (relative intensity,
%): 384 (M+, 37), 192 (100), 165 (61), 135 (35). Anal. Calcd
for C21H20O7: C, 65.62; H, 5.24. Found: C, 65.69; H, 5.12.
(3R*,4R*)-3-[3,4-(Met h ylen ed ioxy)b en zyl]-4-[(rS*)-r-
h yd r oxy-3,4-d im eth oxyben zyl]-γ-bu tyr ola cton e (11a ). To
the solution of the ketone 10a (10.0 g, 26.1 mmol) in THF (150
mL) was added dropwise L-Selectride (1.0 M in THF, 28.6 mL,
28.6 mmol) at -78 °C, and stirring was continued for 5 h at
-20 °C. The mixture was quenched by the addition of AcOH
(1.73 mL, 28.7 mmol) and concentrated. The residue was
diluted with AcOEt (100 mL) and washed with water and
brine, and dried over MgSO4. Evaporation of the solvent
provided the crude product, which was purified by silica gel
column chromatography using CHCl3/acetone (10:1) as the
eluent to afford 11a as the sole diastereomer (9.2 g, 92% yield)
(m, 3H), 3.40-3.65 (m, 2H), 3.80 (s, 3H), 3.86 (s, 3H), 5.16 (d,
1H, J ) 9.2 Hz), 5.92 (s, 2H), 6.56-6.88 (m, 6H); MS m/ z
(relative intensity, %): 386 (M+, 38), 194 (100), 135 (62). Anal.
Calcd for C21H22O7: C, 65.28; H, 5.74. Found: C, 65.08; H,
5.65
Ster eoselective Deu ter ia tion of th e Meta l En ola te of
3a . Deuteriation of 3a (430 mg, 1.00 mmol in 5 mL) was
carried out as described above for 1h and 2h . Compound 4d
and 4′d was used directly for transformation into 1h and 2h .
(3R*,4S*,5R*)-3-Meth yl-3-[3,4-(m eth ylen edioxy)ben zyl]-
4-[[(m eth oxym eth yl)oxy]m eth yl]-5-(3,4-dim eth oxyph en yl)-
γ-bu tyr ola ceton e (4e). Methylation of 3a (500 mg, 1.16
mmol) was carried out as described above for 1i. Crude
product of 4e was purified by silica gel column chromatography
using hexane/CHCl3/AcOEt (10:10:1) as the eluent to afford
4e (450 mg, 87%): mp 101-2 °C (AcOEt-hexane); IR (KBr)
1
2945, 1757 cm-1; 400 MHz H NMR (δ in CDCl3) 1.41 (s, 3H),
2.51-2.71 (m, 1H), 2.71 (d, 1H, J ) 13.6 Hz), 3.29 (d, 1H, J )
13.6 Hz), 3.36 (s, 3H), 3.44 (dd, 1H, J ) 4.6, 9.8 Hz), 3.61-
3.76 (m, 1H), 3.67 (s, 3H), 3.84 (s, 3H), 4.55 (d, 1H, J ) 6.6
Hz), 4.58 (d, 1H, J ) 6.6 Hz), 4.83 (d, 1H, J ) 10.2 Hz), 5.89
(d, 1H, J ) 1.3 Hz), 5.90 (d, 1H, J ) 1.3 Hz), 6.26 (d, 1H, J )
2.0 Hz), 6.62 (dd, 1H, J ) 1.9, 8.1 Hz), 6.72 (s, 1H), 6.74 (s,
2H), 6.78 (s, 1H); MS m/ z (relative intensity, %): 444 (M+,
11), 135 (100), 45 (38). Anal. Calcd for C24H28O8: C, 64.85;
H, 6.35. Found: C, 64.72; H, 6.19.
Ethylation was conducted in the same manner described
above.
(3R*,4S*,5R*)-3-Eth yl-3-[3,4-(m eth ylen ed ioxy)ben zyl]-
4-[[(m eth oxym eth yl)oxy]m eth yl]-5-(3,4-dim eth oxyph en yl)-
γ-bu tyr ola cton e (4f): 89% yield from 3a ; mp 112-3 °C
1
as a syrup: IR (KBr) 3500, 1765 cm-1; H NMR (δ in CDCl3)
(AcOEt-hexane); IR (KBr) 2945, 1757 cm-1 1H NMR (δ in
;
2.08 (d, 1H, J ) 2.7 Hz), 2.50-2.70 (m, 1H), 2.80-3.10 (m,
3H), 3.85 (s, 3H), 3.88 (s, 3H), 3.98 (dd, 2H, J ) 1.7, 7.8 Hz),
4.66 (dd, 1H, J ) 2.7, 6.4 Hz), 5.85-5.95 (m, 2H), 6.50-6.85
(m, 6H); MS m/ z (relative intensity, %): 386 (M+, 25), 167
(100), 135 (54). Anal. Calcd for C21H22O7: C, 65.28; H, 5.74.
Found: C, 65.21; H, 5.63.
CDCl3) 1.16 (t, 3H, J ) 7.5 Hz), 1.69-2.03 (m, 2H), 2.62 (d,
1H, J ) 13.5 Hz), 2.63-2.79 (m, 1H), 3.35 (s, 3H), 3.38 (d, 1H,
J ) 13.6 Hz), 3.43 (dd, 1H, J ) 4.6, 9.8 Hz), 3.65 (s, 3H), 3.74
(dd, 1H, J ) 9.6, 10.9 Hz), 3.84 (s, 3H), 4.54 (d, 1H, J ) 6.6
Hz), 4.58 (d, 1H, J ) 6.6 Hz), 4.81 (d, 1H, J ) 10.5 Hz), 5.84-
5.94 (m, 2H), 6.21 (d, 1H, J ) 1.9 Hz), 6.60 (dd, 1H, J ) 2.0,
8.1 Hz), 6.72 (d, 1H, J ) 8.2 Hz), 6.75 (br s, 2H), 6.81 (br s,
1H); MS m/ z (relative intensity, %): 458 (M+, 19), 135 (100).
Anal. Calcd for C25H30O8: C, 65.49; H, 6.60. Found: C, 65.28;
H, 6.51.
(3S*,4S*,5R*)-3-Hyd r oxy-3-[3,4-(m eth ylen ed ioxy)ben -
zyl]-4-[[(m et h oxym et h yl)oxy]m et h yl]-5-(3,4-d im et h ox-
yp h en yl)-γ-bu tyr ola cton e (4a ). Hydroxylation of 3a (7.00
g, 16.3 mmol) was carried out as described above for 1d . Crude
mixture of 4a , which was purified by silica gel column
chromatography using hexane/CHCl3/AcOEt (5:5:3) as the
eluent to afford 4a (6.50 g, 89%) as a colorless crystalline
solid: mp 122-4 °C (AcOEt-i-Pr2O); IR (KBr) 3457, 1775
cm-1; 1H NMR (δ in CDCl3) 2.43-2.59 (m, 1H), 3.05 (d, 1H, J
) 13.5 Hz), 3.16 (d, 1H, J ) 13.4 Hz), 3.37 (s, 3H), 3.47 (s,
1H), 3.55 (dd, 1H, J ) 4.2, 10.1 Hz), 3.76 (s, 3H), 3.79 (dd, 1H,
J ) 3.8, 10.1 Hz), 3.87 (s, 3H), 4.59 (d, 1H, J ) 6.6 Hz), 4.63
(d, 1H, J ) 6.5 Hz), 5.26 (d, 1H, J ) 8.3 Hz), 5.92 (s, 2H), 6.46
(d, 1H, J ) 13.4 Hz), 6.61-6.84 (m, 5H); MS m/ z (relative
intensity, %): 446 (M+, 18), 238 (52), 193 (71), 165 (80), 135
(100). Anal. Calcd for C23H26O9: C, 61.88; H, 5.87. Found:
C, 61.71; H, 5.73.
(3R*,4S*)-3-Hyd r oxy-3-[3,4-(m et h ylen ed ioxy)b en zyl]-
4-(3,4-d im eth oxyben zyl)-γ-bu tyr ola cton e (2d ). The lac-
tone 4a (0.72 g, 1.61 mmol) was dissolved in AcOH (10 mL),
and 10% Pd/C (1.4 g) and concd H2SO4 (0.1 mL) were added
to the solution. The mixture was stirred under hydrogen (3.5
atm, rt) for 48 h followed by filtration and evaporation to give
a crude product (13a ). To a solution of 13a in a mixture of
THF (3 mL), AcOH (3 mL), and water (3 mL) was added a
catalytic amount of concd H2SO4, and the mixture was stirred
for 3 h at 40 °C. The reaction mixture was cooled to rt, poured
into water, extracted with AcOEt, dried over MgSO4, and
evaporated in vacuo. The residue was chromatographed on
silica gel with hexane/CHCl3/AcOEt (5:5:3) as the eluent to
afford 2d as a solid in 85% yield. Recrystallization from
AcOEt-hexane furnished pure 2d . The diastereoselectivity
was determined by HPLC analysis with 35:65 CH3CN-H2O
as the mobile phase: mp 140-1 °C (AcOEt); IR (KBr) 3520,
(3R*,4S*,5R*)-3-[3,4-(Meth ylen edioxy)ben zyl]-4-[[(m eth -
oxym eth yl)oxy]m eth yl]-5-(3,4-d im eth oxyp h en yl)-γ-bu ty-
r ola cton e (3a ). To an ice-cooled solution of 11a (5.00 g, 13.0
mmol) in DMF (50 mL) was added sodium hydride (544 mg,
13.7 mmol), and the mixture was stirred at the same temper-
ature for 1 h. The mixture was quenched by the addition of 2
N HCl (6.8 mL), and the DMF was removed in vacuo. The
residue was extracted with AcOEt, and the combined organic
layers were washed with water and brine and dried over
MgSO4. Evaporation of the solvent provided the crude product
(12a ), which was not purified but used directly for the
synthesis of 3a . The crude product 12a (5.00 g, 13.0 mmol)
and diisopropylethylamine (2.90 mL, 16.9 mmol) were dis-
solved in DMF (30 mL), and the solution was ice-cooled. To
the mixture was added chloromethyl methyl ether (1.28 mL,
16.9 mmol), and the resulting mixture was stirred for 12 h at
room temperature. The mixture was poured into water and
extracted with AcOEt. The combined organic layers were
washed with water, 10% citric acid, saturated aqueous NaH-
CO3, and brine and dried over MgSO4. Evaporation of the
solvent provided the crude oil, which was purified by silica
gel column chromatography using hexane/CHCl3/AcOEt (5:5:
3) as the eluent to afford 3a (4.50 g) in 80% yield: mp 146-7
°C (AcOEt); IR (KBr) 1761 cm-1; 1H NMR (δ in CDCl3) 2.12-
2.40 (m, 1H), 2.96-3.21 (m, 3H), 3.30 (dd, 1H, J ) 3.8, 10.3
Hz), 3.34 (s, 3H), 3.44 (dd, 1H, J ) 3.7, 10.3 Hz), 3.79 (s, 3H),
3.87 (s, 3H), 4.51 (d, 1H, J ) 6.6 Hz), 4.59 (d, 1H, J ) 6.6 Hz),
5.15 (d, 1H, J ) 9.2 Hz), 5.92 (s, 2H), 6.58 (d, 1H, J ) 1.7 Hz),
6.63-6.86 (m, 5H); MS m/ z (relative intensity, %): 430 (M+,
62), 238 (37), 193 (45), 165 (56), 135 (100). Anal. Calcd for
C23H26O8: C, 64.18; H, 6.09. Found: C, 64.10; H, 6.04.
(3S*,4S*,5R*)-3-[3,4-(Met h ylen ed ioxy)b en zyl]-4-(h y-
d r oxym e t h yl)-5-(3,4-d im e t h oxyp h e n yl)-γ-b u t yr ola c-
ton e (12a ). An analytical sample of 12a was obtained in 75%
yield from 11a by silica gel column chromatography using
hexane/CHCl3/AcOEt (1:1:1) as the eluent: mp 138-9 °C
(AcOEt-hexane); IR (KBr) 3461, 1737 cm-1
;
1H NMR (δ in
CDCl3) 1.42 (t, 1H, J ) 4.6 Hz), 2.18-2.39 (m, 1H), 2.91-3.21

6930 J . Org. Chem., Vol. 61, No. 20, 1996
Moritani et al.
1782 cm-1; 1H NMR (δ in CDCl3) 2.64 (dd, 1H, J ) 11.3, 13.3
Hz), 2.71 (s, 1H), 2.82-3.05 (m, 3H), 3.13 (dd, 1H, J ) 3.9,
13.3 Hz), 3.87 (s, 3H), 3.88 (s, 3H), 3.93 (dd, 1H, J ) 10.2,
10.2 Hz), 4.20 (dd, 1H, J ) 7.7, 9.2 Hz), 5.96 (s, 2H), 6.63-
6.87 (m, 6H); MS m/ z (relative intensity, %): 368 (M+, 10),
151 (9), 135 (100). Anal. Calcd for C21H22O7: C, 65.28; H, 5.74.
Found: C, 65.24; H, 5.61.
6.90 (m, 6H); 13C NMR (δ in CDCl3) 32.18, 38.33, 48.21, 55.93,
55.98, 69.29, 75.87, 101.09, 108.56, 108.75, 111.36, 113.76,
121.36, 122.70, 125.60, 131.60, 146.56, 148.13, 148.75, 149.05,
177.80; MS m/ z (relative intensity, %): 386 (M+, 19), 151 (100),
135 (23). Anal. Calcd for C21H22O7: C, 65.28; H, 5.74.
Found: C, 65.11; H, 5.81.
X-r a y An a lyses.25 X-ray analyses were performed by a
AFC5R (Rigaku) with CuKR radiation. The structures were
solved by a direct method (SHELXS-86 or MULTAN-80), and
the atomic parameters were refined using a full matrix least-
square method with anisotropic temperature factors for non
H atoms. Crystal data of 1i: a ) 6.79(11), b ) 9.91(16), c )
28.32(13) Å, R ) 90.0(0), â ) 93.1(11), γ ) 90.0(0)°, U ) 1904.3-
(41) Å3, monoclinic, P21/c (Z ) 4), Dx ) 1.34 g/cm3, final R )
0.054 (Rw ) 0.038). Crystal data of 12a : a ) 17.81(1), b )
7.56(1), c ) 14.32(2) Å, R ) 90.0(0), â ) 91.2(1), γ ) 90.0(0)°,
U ) 1928.1(3) Å3, monoclinic, P21/a (Z ) 4), Dx ) 1.33 g/cm3,
final R ) 0.056 (Rw ) 0.057). Crystal data of 2i: a ) 16.77(2),
b ) 9.53(1), c ) 12.82(2) Å, R ) 90.0(0), â ) 108.44(1), γ )
90.0(0)°, U ) 1942.0(4) Å3, monoclinic, P21/c (Z ) 4), Dx ) 1.32
g/cm3, final R ) 0.072 (Rw ) 0.069).
(3S*,4R*)-3-Deu ter io-3-[3,4-(m eth ylen ed ioxy)ben zyl]-
4-(3,4-d im eth oxyben zyl)-γ-bu tyr ola cton e (2h ): 76% yield
from 4d ; mp 102-3 °C (AcOEt-hexane); IR (KBr) 1773 cm-1
;
1H NMR (δ in CDCl3) 2.32 (dd, 1H, J ) 12.3, 13.3 Hz), 2.60-
3.13 (m, 3H), 3.22 (d, 1H, J ) 14.9 Hz), 3.84 (s, 3H), 3.85 (s,
3H), 3.96-4.12 (m, 2H), 5.96 (s, 2H), 6.53 (d, 1H, J ) 1.9 Hz),
6.61 (dd, 1H, J ) 1.9, 8.1 Hz), 6.71-6.87 (m, 4H); MS m/ z
(relative intensity, %): 371 (M+, 51), 151 (67), 135 (100).
(3S*,4R*)-3-Meth yl-3-[3,4-(m eth ylen ed ioxy)ben zyl]-4-
(3,4-d im eth oxyben zyl)-γ-bu tyr ola cton e (2i). 84% yield
from 4e; mp 141-2 °C (AcOEt-hexane); IR (KBr) 2909, 1773
1
cm-1; H NMR (δ in CDCl3) 1.21 (s, 3H), 2.47-2.78 (m, 2H),
2.73 (d, 1H, J ) 14.0 Hz), 2.88 (d, 1H, J ) 14.1 Hz), 2.96 (dd,
1H, J ) 4.5, 13.2 Hz), 3.78 (dd, 1H, J ) 9.0, 9.7 Hz), 3.87 (s,
3H), 3.88 (s, 3H), 4.08 (dd, 1H, J ) 7.3, 9.1 Hz), 5.95 (s, 2H),
6.61-6.87 (m, 6H); MS m/ z (relative intensity, %): 384 (M+,
15), 151 (23), 135 (100). Anal. Calcd for C22H24O6: C, 68.74;
H, 6.29. Found: C, 68.29; H, 6.35.
Ack n ow led gm en t. We thank Dr. A. Kinumaki, Dr.
T. Da-te, and Mr. K. Okamura of our company who
carried out the NMR analyses and the X-ray crystal-
lographic analyses.
(3S*,4R*)-3-Eth yl-3-[3,4-(m eth ylen edioxy)ben zyl]-4-(3,4-
d im eth oxyben zyl)-γ-bu tyr ola cton e (2j): 83% yield from 4f;
mp 134-5 °C (AcOEt-hexane); IR (KBr) 2938, 1771 cm-1; 1H
NMR (δ in CDCl3) 0.92 (t, 3H, J ) 7.4 Hz), 1.38-1.60 (m, 1H),
1.70-1.92 (m, 1H), 2.62-3.00 (m, 5H), 3.67-3.80 (m, 1H), 3.87
(s, 3H), 3.88 (s, 3H), 4.03-4.15 (m, 1H), 5.95 (s, 2H), 6.52-
6.88 (m, 6H); MS m/ z (relative intensity, %): 398 (M+, 48),
151 (60), 135 (100). Anal. Calcd for C23H26O6: C, 69.33; H,
6.58; Found: C, 69.36; H, 6.53.
Su p p or tin g In for m a tion Ava ila ble: Compound charac-
terization data for 5b, 1m -o, 1e-g, 2e-g, 10b,c, 11b,c, 3b,c,
4b,c, 2a and the ORTEP diagram for 12a (7 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.
(3R*,4S*)-3-H yd r oxy-3-(3,4-d im et h oxyb en zyl)-4-[3,4-
(m eth ylen ed ioxy)ben zyl]-γ-bu tyr ola cton e [2c: (()-gu a y-
a d equ iol]: 76% yield from 4b; mp 151-2 °C (AcOEt); IR (KBr)
3415, 1762 cm-1; 1H NMR (δ in CDCl3) 2.64 (dd, 1H, J ) 11.3,
13.1 Hz), 2.71 (s, 1H), 2.80-3.00 (m, 1H), 2.97 (s, 2H), 3.12
(dd, 1H, J ) 3.9, 13.1 Hz), 3.86 (dd, 1H, J ) 9.2, 10.2 Hz),
3.88 (s, 6H), 4.19 (dd, 1H, J ) 7.7, 9.1 Hz), 5.95 (s, 2H), 6.60-
J O9601932
(25) The author has deposited atomic coordinates for 1d , 2d , and
13d with the Cambridge Crystallographic Data Centre. The coordi-
nates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK.