Oxidative Homocoupling of Chiral 3-Arylpropanoic Acid Derivatives. Application to Asymmetric Synthesis of Lignans

Article abstract of DOI:10.1021/jo991317o

The oxidative homocouplings of lithium enolates of (4S)-3-(3-arylpropanoyl)-4-isopropyl-2-oxazolidinones and (4R,5S)-1-(3-arylpropanoyl)-3,4-dimethyl-5-phenyl-2-imidazolidinones gave the corresponding R,R-dimers stereoselectively with TiCl₄, Ph

Full text of DOI:10.1021/jo991317o

464
J . Org. Chem. 2000, 65, 464-468
Oxid a tive Hom ocou p lin g of Ch ir a l 3-Ar ylp r op a n oic Acid
Der iva tives. Ap p lica tion to Asym m etr ic Syn th esis of Lign a n s
Naoki Kise,* Takako Ueda, Kimikage Kumada, Yuichi Terao, and Nasuo Ueda
Department of Biotechnology, Faculty of Engineering, Tottori University, Tottori 680-0945, J apan
Received August 19, 1999
The oxidative homocouplings of lithium enolates of (4S)-3-(3-arylpropanoyl)-4-isopropyl-2-oxazo-
lidinones and (4R,5S)-1-(3-arylpropanoyl)-3,4-dimethyl-5-phenyl-2-imidazolidinones gave the cor-
responding R,R-dimers stereoselectively with TiCl4, PhI(OAc)2, or CuCl2 as an oxidant. The
stereoselectivity can be explained by a radical coupling mechanism. Optically active dibenzylbu-
tyrolactone lignans, such as (-)-hinokinin and (-)-dimethylmatairesinol, and dibenzylbutanediol
lignans, such as (-)-dihydrocubebin and (-)-dimethylsecoisolariciresinol, were synthesized from
the major R,R-dimers. The oxidative coupling of (4R,5S)-1-(3-arylpropanoyl)-3,4-dimethyl-5-phenyl-
2-imidazolidinones with LDA-I2 gave R,S-dimers mainly, and this result can be explained by an
SN2 mechanism.
Sch em e 1
In tr od u ction
Dibenzylbutyrolactones, such as (-)-hinokinin and (-)-
enterolactone, and dibenzylbutanediols, such as (-)-
dihydrocubebin and (-)-enterodiol, are one of the classes
of lignans and attract considerable interest due to their
biological activities.1 Recently, a number of strategies for
the asymmetric synthesis of these classes of lignans have
been reported.2 Optically active 3,4-dibenzylsuccinic acids
are useful precursors of dibenzylbutyrolactone and diben-
zylbutanediol lignans (Scheme 1). Oxidative homocou-
pling of 3-phenylpropanoic acids is an effective method
for the synthesis of 3,4-dibenzylsuccinic acids.3 We have
reported the first asymmetric synthesis of 3,4-dibenzyl-
succinic acids by the oxidative homocoupling of (4S)-3-
(3-arylpropanoyl)-4-isopropyl-2-oxazolidinones with LDA-
TiCl4 and its application to the synthesis of (-)-hinokinin
(Scheme 2).4 After that, Helmchen’s group reported the
oxidative coupling of (4S,5R)-1-(3-arylpropanoyl)-3,4-
dimethyl-5-phenyl-2-imidazolidinones and the synthesis
of ent-hinokinin from the adducts.5 Herein we report full
details of our study on the stereoselective oxidative
homocoupling of optically active 3-arylpropanoic acid
derivatives.6,7 We also present the asymmetric synthesis
Sch em e 2
(1) (a) Ayres, D. C.; Loike, J . D. Lignans; Cambridge University
Press: Cambridge, 1990. (b) Ward, R. S. Tetrahedron 1990, 46, 5029.
(2) (a) Rehnberg, N.; Magnusson, G. J . Org. Chem. 1990, 55, 4340.
(b) Yoda, H.; Naito, S.; Takabe, K.; Tanaka, N.; Hosoya, K. Tetrahedron
Lett. 1990, 31, 7623. (c) Itoh, T.; Chika, J .; Takagi, Y.; Nishiyama, S.
J . Org. Chem. 1993, 58, 5717. (d) Pelter, A.; Ward, R. S.; J ones, D. M.;
Maddocks, P. J . Chem. Soc., Perkin Trans. 1 1993, 2621, 2631. (e) van
Oeveren, A.; J ansen, F. G. A.; Feringa, B. L. J . Org. Chem. 1994, 59,
5999. (f) Moritani, Y.; Fukushima, C.; Ukita, T.; Miyagishima, T.;
Ohmizu, H.; Iwasaki, T. J . Org. Chem. 1966, 61, 6922. (g) Bode, J . W.;
Doyle, M. P.; Protopopova, M. N.; Zhou, Q. J . Org. Chem. 1996, 61,
9146. (h) Brinlsma, J .; van der Deen, H.; van Overen, A.; Feringa, B.
L. J . Chem. Soc., Perkin Trans. 1 1998, 4159.
of dibenzylbutyrolactone and dibenzylbutanediol lignans
from the obtained enantiomerically pure adducts.
(3) Belletire, J . L.; Fry, D. F. J . Org. Chem. 1987, 52, 2549; 1988,
53, 4724.
Resu lts a n d Discu ssion
(4) Kise, N.; Tokioka, K.; Aoyama, Y.; Matsumura, Y. J . Org. Chem.
1995, 60, 1100.
Oxid a t ive H om ocou p lin g of (4S)-3-(3-Ar ylp r o-
p a n oyl)-4-isop r op yl-2-oxa zolid in on es. We have al-
ready reported that the oxidative homocoupling of chiral
3-(arylacetyl)-2-oxazolidinones took place stereospecifi-
(5) Langer, T.; Illich, M.; Helmchen, G. Synlett 1996, 1137.
(6) The oxidative intermolecular couplings of chiral oxazolidine,6a
imidazolidinone,6b and oxazolidinone6c derivatives of propanoic and
butyric acids have been reported: (a) Porter, N. A.; Su, Q.; Harp, J .
J .; Rosenstein, I. J .; McPhail, A. T. Tetrahedron Lett. 1993, 34, 4457.
(b) Langer, T.; Illich, M.; Helmchen. Tetrahedron Lett. 1995, 36, 4409.
(c) Kim, J . W.; Lee, J .-J .; Lee, S.-H.; Ahn, K.-H. Synth. Commun. 1998,
28, 1287.
(7) The oxidative intramolecular coupling of chiral 4-oxoimidazoli-
dine derivatives of pimelic acid has been reported: Studer, A.;
Hintermann, T.; Seebach, D. Helv. Chim. Acta 1995, 78, 1185.
10.1021/jo991317o CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/29/1999

Homocoupling of 3-Arylpropanoic Acid Derivatives
J . Org. Chem., Vol. 65, No. 2, 2000 465
Ta ble 1. Oxid a tive Cou p lin g of Ch ir a l
3-(3-Ar ylp r op a n oyl)-2-oxa zolid in on es 1
Ta ble 2. Oxid a tive Cou p lin g of Ch ir a l
1-(3-Ar ylp r op a n oyl)-2-im id a zolid in on es 3
run
3
oxidant
TiCl4
4
% yield of 2a
R,R:R,S of 2b
run
1
oxidant
TiCl4
2
% yield of 2a
R,R:R,S of 2b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
3a
3a
3a
3a
3b
3b
3b
3b
3c
3c
3c
3c
3d
3d
3d
3d
4a
4a
4a
4a
4b
4b
4b
4b
4c
4c
4c
4c
4d
4d
4d
4d
55
79
52
76
52
82
63
80
43
78
52
65
48
78
45
57
>98:2
74:26
>98:2
40:60
84:16
74:26
92:8
30:70
87:13
81:19
88:12
11:89
92:8
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
1d
2a
2a
2a
2a
2b
2b
2b
2c
2c
2c
2d
2d
2d
67
69
55
38
55
69
42
43
80
51
71
81
41
85:15
85:15
80:20
57:43
85:15
78:22
75:25
86:14
83:17
78:22
87:13
85:15
83:17
PhI(OAc)2
c
PhI(OAc)2
CuCl2
I2
c
c
CuCl2
I2
c
TiCl4
TiCl4
PhI(OAc)2
c
PhI(OAc)2
CuCl2
I2
c
c
CuCl2
TiCl4
TiCl4
PhI(OAc)2
PhI(OAc)2
c
c
CuCl2
CuCl2
I2
c
TiCl4
PhI(OAc)2
TiCl4
c
CuCl2
PhI(OAc)2
77:23
92:8
25:75
c
CuCl2
I2
a
b
Isolated yields. Determined by 1H NMR analysis. c In the
c
presence of DMPU.
a
b
Isolated yields. Determined by 1H NMR analysis. c In the
cally by treatment with an amine-TiCl4 couple.4,8 Un-
fortunately, 3-(3-arylpropanoyl)-2-oxazolidinones 1 did
not react with the amine-TiCl4 couple probably due to
the low basicity of the amine. Therefore, LDA was
employed as a base in place of the amine to generate
lithium enolates of 1. The results of the oxidative
homocoupling of 1a-d with several LDA-oxidant couples
are shown in Table 1. The oxidative homocoupling of the
lithium enolates of (4S)-4-isopropyl-3-(3-phenylpropanoyl)-
2-oxazolidinone (1a ) with TiCl4 gave the dimer 2a in 67%
yield and R,R:R,S ) 85:15 selectivity (run 1). A similar
result was obtained with PhI(OAc)2 as an oxidant (run
2). The reactions with CuCl2 and I2 proceeded in the
presence of DMPU as an additive, although the yields
and selectivities were low (runs 3 and 4). Aryl-substituted
substrates 1b-d were also subjected to the oxidative
homocoupling (runs 5-13). Generally, PhI(OAc)2 as an
oxidant gave the best yields of 2, while TiCl4 resulted in
the best R,R-selectivities of 2. The absolute configurations
of the major isomers of 2b-d were determined to be R,R
by their transformation to the known compounds as
described below. The R,R-configuration of the major
isomer of 2a was assigned by the correlation of its 1H
NMR spectrum with those of (R,R)-2b-d .
Oxid a tive Hom ocou p lin g of (4R,5S)-1-(3-Ar yl-
p r op a n oyl)-3,4-d im e t h yl-5-p h e n yl-2-im id a zolid i-
n on es. Helmchen’s group has reported that the LDA-
TiCl4 couple gave the best results for the oxidative
homocoupling of (4S,5R)-3,4-dimethyl-1-(3-(3,4-methyl-
en edioxyph en yl)pr opa n oyl)-5-ph en yl-2-im ida zolidi-
none.5 We examined the oxidative coupling of (4R,5S)-
1-(3-arylpropanoyl)-3,4-dimethyl-5-phenyl-2-imidazolidi-
nones 3a -d with several LDA-oxidant couples, similarly
to the above-described reactions of 1. According to the
results summarized in Table 2, it was found that the
LDA-CuCl2 or LDA-TiCl4 couple gave the best R,R-
presence of DMPU.
Sch em e 3
selectivities and the LDA-PhI(OAc)2 couple afforded the
best yields of the adducts 4. It is noted that R,S-isomers
of 4 were formed mainly with the LDA-I2 couple. In all
cases, the formation of S,S-isomers of 4 could not be
1
detected by H NMR spectra of the crude products. The
absolute configurations of (R,R)-4b-d were confirmed by
their transformation to the known compounds (vide
infra). The stereoconfiguration of (R,R)-4a was assigned
by the correlation of its H NMR spectrum with those of
(R,R)-4b-d .
R ea ct ion Mech a n ism of Oxid a t ive H om ocou -
p lin g. The R,R-selectivity in the oxidative homocouplings
of 1 and 3 can be explained by a radical coupling
mechanism9 (Scheme 3). It is well-known that the treat-
ment of 3-acyl-2-oxazolidinones or 1-acyl-2-imidazolidi-
nones with LDA affords Li-chelated (Z)-enolates.10 In the
reaction of 1 or 3 with LDA-TiCl4, it is likely that the
initially formed lithium enolate (5, M ) Li) is trans-
1
(8) Kise, N.; Kumada, K.; Terao, Y.; Ueda, N. Tetrahedron 1998,
54, 2697.
(9) Renaud, P.; Fox, M. A. J . Org. Chem. 1988, 53, 3745.

466 J . Org. Chem., Vol. 65, No. 2, 2000
Kise et al.
Sch em e 4
Sch em e 6
Sch em e 5
Sch em e 7
formed to titanium enolate (5, M ) TiCl3).11 The metal-
chelated (Z)-enolate 5 is subsequently oxidized to radical
intermediate 6 by a single electron-transfer (SET) pro-
cess. The syn-Z-type radicals 6 couple each other at the
less hindered â side (si face) to give the R,R-isomer of 2
or 4 stereoselectively. It seems that the aryl group in the
radical intermediate 6 may inhibit the homocoupling at
the si face and decrease the R,R-selectivity. In fact, the
oxidative homocouplings of 8, less bulky substrates than
1 (Ar f H, Me), with LDA-TiCl4 gave the dimer 9 with
>95% R,R-selectivity, higher than those in the reactions
of 1 (85-87% R,R-selectivity) (Scheme 4).
On the other hand, there is an alternative mechanism9
for the oxidative homocoupling with LDA-I2 (Scheme 5).
That is, iodide 7 is formed by the attack of iodine on the
radical 6 from the less hindered â side (si face), and then
the iodide 7 reacts with 5 at the si face to yield the R,S-
isomer of 2 or 4. The increase of R,S-selectivity in the
oxidative homocouplings of 1 and 3 with I2 can be
explained by the SN2 mechanism. The oxidative coupling
of 8a with LDA-I2, however, gave the dimer 9 with >95%
R,R-selectivity (Scheme 4). This result shows that the
radical coupling mechanism is predominant in the reac-
tion of 8a , since 8a is less bulky than 1 (Ar f H). Similar
high stereoselectivities have been reported in the oxida-
tive homocoupling of (4S,5R)-3,4-dimethyl-5-phenyl-1-
propanoyl-2-imidazolidinone with LDA-I2.6b
Syn th esis of Diben zylbu tyr ola cton es. The R,R-
isomers of 2 were hydrolyzed with LiOOH in THF/H2O
to give (2R,3R)-2,3-dibenzylsuccinic acids (R,R)-10 (Scheme
6). The hydrolysis of the R,R-isomers of 4 with LiOH in
refluxing THF/H2O also afforded (R,R)-10. Naturally,
hydrolysis of the R,S-isomers of 2 and 4 gave meso-2,3-
dibenzylsuccinic acids meso-10. The treatment of (R,R)-
10b with Ac2O and the subsequent reduction of the
resultant anhydride with NaBH4 in THF gave (-)-
hinokinin (11b)12 in 76% yield. (-)-Dimethylmatairesinol
(11c)13 and 11d 14 were prepared by the same method
from (R,R)-10c and (R,R)-10d , respectively. It has been
reported that the demethylation of 11d with BBr3 gave
(-)-enterolactone (Ar in 11 ) 3-C6H4OH).14
Syn th esis of Diben zylbu ta n ed iols. The R,R-isomers
of 10 were transformed to (2R,3R)-2,3-dibenzylbutane-
diols (R,R)-12 by reduction with LiAlH4 in refluxing THF
(Scheme 7). Alternatively, the treatment of the R,R-
isomers of 4 with LiBH4 in THF afforded (R,R)-12. (-)-
Dihydrocubebin ((R,R)-12b)15 and (-)-dimethylsecoiso-
lariciresinol ((R,R)-12c)13 were obtained by these methods.
(-)-Dihydrocubebin ((R,R)-12b ) can be transformed to
(10) (a) Evans, D. A. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press: New York, 1984; Vol. III, p 1. (b) Evans, D. A.; Bartoli,
J .; Shih, T. L. J . Am. Chem. Soc. 1981, 103, 2127. (c) Evans, D. A.;
Ennis, M. D.; Mathre, D. J . J . Am. Chem. Soc. 1982, 104, 1737. (d)
Cardillo, G.; D’Amico, A.; Orena, M.; Sandri, S. J . Org. Chem. 1988,
53, 2354.
(12) Hawworth, R. D.; Woodcock, D. J . Chem. Soc. 1938, 1985.
(13) Takaoka, D.; Takamatsu, N.; Saheki, Y.; Kono, K.; Nakaoka,
C.; Hiroi, M. Nippon Kagaku Kaishi 1975, 12, 2192; Chem. Abstr. 1976,
84, 71488k.
(14) Yoda, H.; Kitayama, H.; Katagiri, T.; Takabe, K. Tetrahedron
1992, 48, 3313.
(11) Reetz, M. T. Organotitanium Reagents in Organic Synthesis;
Springer-Verlag: Berlin, 1986.
(15) Batterbee, J . E.; Burden, R. S.; Crombie, L.; Whiting, D. A. J .
Chem. Soc. C 1969, 2470.

Homocoupling of 3-Arylpropanoic Acid Derivatives
J . Org. Chem., Vol. 65, No. 2, 2000 467
quenched with 1 M HCl (40 mL) and extracted with ether (3
× 20 mL). The R,R- and R,S-dimers of 2a , 2b, and 4a -d were
isolated by column chromatography on silica gel. The R,R-
dimer of 2c could be isolated by recrystallization of the
diastereomeric mixtures from hexanes-ethyl acetate. The R,R-
dimer of 2d was purified by the repetition of column chroma-
tography on silica gel. The R,S-dimers of 2c and 2d could not
be purified.
Sch em e 8
Oxid a tive h om ocou p lin g of 1 (3) w ith LDA-P h I(OAc)2
was similarly performed using PhI(OAc)2 (0.78 g, 2.4 mmol)
in place of TiCl4. After addition of PhI(OAc)2, the mixture was
stirred for 12 h at room temperature.
Oxid a tive Hom ocou p lin g of 1 (3) w ith LDA-Cu Cl2. To
a solution of LDA (2.4 mmol) in hexane-THF (5 mL) was
added a solution of 1 (3) (2.0 mmol) in THF (5 mL) dropwise
at -78 °C. After the solution was stirred for 15 min, CuCl2
(0.32 g, 2.4 mmol) and DMPU (0.5 mL) were added to the
mixture at this temperature successively. The mixture was
allowed to warm to room temperature, stirred for 12 h, and
then quenched with 1 M HCl (40 mL). The products were
isolated as described above.
Oxid a tive Hom ocou p lin g of 1 (3) w ith LDA-I2. To a
solution of LDA (2.4 mmol) in hexane-THF (5 mL) was added
a solution of 1 (3) (2.0 mmol) in THF (5 mL) dropwise at -78
°C. After the solution was stirred for 15 min, a solution of I2
(307 mg, 1.2 mmol) and DMPU (0.5 mL) in THF (5 mL) was
added to the mixture at this temperature. After being stirred
for a further 30 min, the mixture was allowed to warm to room
temperature, stirred for 6 h, and then quenched with 1 M HCl
(40 mL). The products were isolated as described above.
Hyd r olysis of 2. To an ice-cooled solution of 2 (1 mmol) in
THF (5 mL) and H2O (4 mL) was added LiOH‚H2O (0.17 g, 4
mmol) and 30% H2O2 (1 mL) successively. The mixture was
stirred at room temperature. After the hydrolysis was complete
(12-24 h), the mixture was treated with 1.5 M Na2SO3 (4 mL)
at 0 °C and extracted with CH2Cl2 (3 × 5 mL). The aqueous
phase was acidified with 3 M HCl (pH < 2) and evaporated in
vacuo. The residue was extracted with CH2Cl2 (30 mL). After
evaporation of CH2Cl2, the diacid 10 was obtained as a white
solid and recrystallized from hexanes-ethyl acetate (80-90%
yield).
(-)-dehydroxycubebin (13)16 and australobailignan-5 (14)17
by the usual procedures (Scheme 8). The reductions of
the R,S-isomers of 4 and 10 yielded meso-2,3-dibenzylbu-
tanediols meso-12.
Con clu sion
The oxidative homocouplings of (4S)-3-(3-arylpropanoyl)-
4-isopropyl-2-oxazolidinones 1 and (4R,5S)-1-(3-arylpro-
panoyl)-3,4-dimethyl-5-phenyl-2-imidazolidinones 3 with
LDA-oxidant couples exhibited high R,R-stereoselectivi-
ties. The choice of oxidant is TiCl4 or PhI(OAc)2 for 1,
while it is TiCl4 or CuCl2 for 3. In the oxidative homo-
coupling of 3, the use of PhI(OAc)2 as an oxidant
increased the yields of the dimers, although the R,R-
selectivities somewhat decreased. In addition, the R,S-
dimers were formed preferentially from 3 using I2 as an
oxidant. Enantiomerically pure dibenzylbutyrolactone
lignans, such as (-)-hinokinin and (-)-dimethylmataires-
inol, and dibenzylbutanediol lignans, such as (-)-dihy-
drocubebin and (-)-dimethylsecoisolariciresinol, were
synthesized from the major R,R-dimers.
Hyd r olysis of 4. To a solution of 4 (1 mmol) in THF (5 mL)
and H2O (5 mL) was added LiOH‚H2O (0.21 g, 5 mmol). The
mixture was refluxed for 24-48 h until almost all of 4 was
consumed (checked by TLC). The diacid 10 was isolated as
described above (70-80% yield).
(1R,2R)-1,2-Bis[(3,4-m eth ylen ed ioxyp h en yl)m eth yl]e-
th a n e-1,2-d ica r boxylic a cid (10b): mp 172-174 °C, lit.12 mp
174-175 °C; [R]20 -12.0 (c 1.08, acetone), lit.12 [R]20 -12.4
Exp er im en ta l Section
Gen er a l Meth od s. Column chromatography was per-
formed on silica gel 60 (Merck). Tetrahydrofuran was distilled
from benzophenone ketyl.
D
D
(c 1.032, acetone).
Syn th esis of Diben zylbu tyr ola cton es 11. To (R,R)-10b
(200 mg, 0.52 mmol) was added Ac2O (4 mL) at 0 °C, and the
resulting mixture was stirred at 0 °C for 15 min. The mixture
was then cooled to - 70 °C and diluted with methanol (12 mL).
The solution was stirred below 0 °C for 10 min. The solvents
were then removed at reduced pressure to give a pale yellow
solid of acid anhydride. To an ice-cooled suspension of NaBH4
(20 mg, 0.53 mmol) in dry THF (2 mL) was slowly added the
crude acid anhydride in dry THF (2 mL). The ice bath was
removed, and stirring was continued for 1 h. The mixture was
acidified carefully with 1 N HCl (1 mL) and then stirred at
room temperature for 1 h. The solvents were removed under
reduced pressure. The residue was purified by column chro-
matography on silica gel (hexanes-ethyl acetate, 2:1) to yield
140 mg (0.40 mmol, 76%) of (-)-hinokinin 11b as a pale yellow
oil. (-)-Dimethylmatairesinol (11c) and 11d were obtained by
the same procedure in 64% and 70% yields, respectively.
Sta r tin g Ma ter ia ls. (4S)-3-(3-Arylpropanoyl)-4-isopropyl-
2-oxazolidinones 1 were prepared from (4S)-4-isopropyl-2-
oxazolidinones and 3-arylpropanoyl chlorides by the reported
methods.18 (4R,5S)-1-(3-Arylpropanoyl)-3,4-dimethyl-5-phenyl-
2-imidazolidinones 3 were obtained similarly from commer-
cially available (4S,5R)-1,5-dimethyl-4-phenyl-2-imidazolidi-
none. The products were purified by column chromatography
on silica gel or recrystallization from hexanes-ethyl acetate.
Oxid a tive Hom ocou p lin g of 1 (3) w ith LDA-TiCl4. To
a solution of LDA (2.4 mmol) in hexane-THF (5 mL) was
added a solution of 1 (3) (2 mmol) in THF (5 mL) dropwise at
-78 °C. After the mixture was stirred for 15 min, TiCl4 was
added (0.26 mL, 2.4 mmol) at this temperature. The temper-
ature was gradually raised to room temperature, and then the
dark blue solution was stirred for 24 h. The mixture was
(-)-Hin ok in in (11b): [R]20 -33.0 (c 0.63, CHCl3), lit.12
D
(16) (a) Anjaneyulu, A. S. R.; Ramaiah, A.; Row: R.; Venkateswarlu,
R. Tetrahedron 1981, 37, 3641. (b) De Carvalho, M. G.; Yoshida, M.;
Gottlieb, O. R.; Gottlieb, H. E. Phytochemistry 1987, 26, 265.
(17) (a) Taylor, W. C.; Ritchie, E.; Murphy, S. T. Aust. J . Chem. 1975,
28. 81. (b) Mahalanabis, K. K.; Mumtaz, M.; Snieckus, V. Tetrahedron
Lett. 1982, 23, 3975.
(18) (a) Gage, J . G.; Evans D. A. Organic Syntheses; Wiley: New
York, 1993; Collect. Vol. VIII, p 339. (b) Ager, D. J .; Allen, D. R.;
Schaad, D. R. Synthesis 1996, 1283.
[R]17 -34.0 (c 0.981, CHCl3).
D
(-)-Dim eth ylm a ta ir esin ol (11c): mp 127-128 °C, lit.13
mp 126-127 °C; [R]20D -33.6 (c 1.05, CHCl3), lit.13 [R]20D -37.5
(c 1.00, CHCl3).
(3R,4R)-3,4-Bis[(3-m eth oxyp h en yl)m eth yl]-3,4,5-tr ih y-
d r ofu r a n -2-on e (11d ): [R]20D -43.7 (c 1.50, CHCl3), lit.14 [R]23
-42.3 (c 0.98, CHCl3).
D

468 J . Org. Chem., Vol. 65, No. 2, 2000
Kise et al.
Red u ction of 10. To an ice-cooled solution of 10 (1 mmol)
in dry THF (10 mL) was added LAH (114 mg, 3 mmol), and
the suspension was refluxed for 12 h. After the usual workup,
the diol 12 was isolated by column chromatography on silica
gel (80-90% yield). (-)-Dihydroxycubebin ((R,R)-12b) and (-)-
dimethylsecoisolariciresinol ((R,R)-12c) were prepared by this
method.
Red u ction of 4. To a solution of 4 (1 mmol) in dry THF
(10 mL) was added LiBH4 (0.11 g, 5 mmol), and the mixture
was stirred at room temperature for 24-48 h until 4 was
completely consumed (checked by TLC). The mixture was
quenched with 1 M HCl (10 mL) and extracted with CH2Cl2
(3 × 10 mL). After evaporation of the solvent, the diol 12 was
isolated by column chromatography on silica gel (70-80%
yield). (-)-Dimethylsecoisolariciresinol ((R,R)-12c) was ob-
tained as a mixture with (4S,5R)-1,5-dimethyl-4-phenyl-2-
imidazolidinone. Therefore, (R,R)-12c was separated with the
imidazolidinone as follows. After silylation of (R,R)-12c by the
treatment with tert-butyldimethylsilane and imidazole in
DMF, the disilylated (R,R)-12c was separated by silica gel
column chromatography and then desilylated with Bu4NF in
THF.
(-)-Dih yd r oxycu bebin ((R,R)-12b): mp 102-104 °C, lit.15
mp 104 °C; [R]20 -35.1 (c 1.05, CHCl3), lit.15 [R]19.8 -32.4 (c
D
D
3.3, CHCl3).
(-)-Dim eth ylsecoisolar icir esin ol ((R,R)-12c): [R]20D -31.7
(c 1.02, CHCl3), lit.13 [R]D -32.9 (CHCl3).
Su p p or tin g In for m a tion Ava ila ble: Compound charac-
terization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O991317O