A general approach to the asymmetric synthesis of lignans: (-)-methyl piperitol, (-)-sesamin, (-)-aschantin, (+)-yatein, (+)-dihydroclusin, (+)-burseran, and (-)-isostegane

Article abstract of DOI:10.1055/s-2002-20967

A highly efficient, diastereo- and enantioselective route was developed to access a great variety of lignans. The asymmetric synthesis of the 2,3-disubstituted γ-butyrolactones 9a-c could be improved in the case of aldol reactions by employing 2.2 equivalents of LiCl as an additive to provide, after purification, highly diastereo- and enantioenriched starting materials for the synthesis of the furofuran lignans (-)-methyl piperitol, (-)-sesamin, and (-)-aschantin. Furthermore, the γ-butyrolactone 15 was converted into dibenzylbutyrolactone lignan (+)-yatein, the dibenzylbutandiol type (+)-dihydroclusin, the tetrahydrofuran type (+)-burseran, and the dibenzocyclooctadiene type (-)-isostegane.

Full text of DOI:10.1055/s-2002-20967

PAPER
515
A General Approach to the Asymmetric Synthesis of Lignans: ( )-Methyl
Piperitol, ( )-Sesamin, ( )-Aschantin, (+)-Yatein, (+)-Dihydroclusin, (+)-Bur-
seran, and ( )-Isostegane
A
General
Approa
i
ch to th
e
e
A
symm
e
t
tric Syn
e
thesis of
L
r
ignans Enders,* Vivien Lausberg, Giuseppe Del Signore, Otto Mathias Berner
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Str. 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 22 January 2002
Dedicated to Professor Hans-Joachim Gais on the occasion of his 60th birthday
tivity. However, it is unsuitable for medicinal use due to
Abstract: A highly efficient, diastereo- and enantioselective route
side-effects and therefore several analogs of 1 have been
was developed to access a great variety of lignans. The asymmetric
prepared in order to enhance its pharmacological profile.
synthesis of the 2,3-disubstituted -butyrolactones 9a c could be
improved in the case of aldol reactions by employing 2.2 equiva-
Among the analogs of (1), some have found clinical
lents of LiCl as an additive to provide, after purification, highly di- use.1,2,4 Moreover, the derivative isodeoxypodophyllotox-
astereo- and enantioenriched starting materials for the synthesis of
the furofuran lignans ( )-methyl piperitol, ( )-sesamin, and ( )-
in (2) shows some biological activity. Furthermore, cer-
tain other compounds belonging to different subgroups of
aschantin. Furthermore, the -butyrolactone 15 was converted into
lignans such as steganacin (3) and burseran (4)5 exhibit
dibenzylbutyrolactone lignan (+)-yatein, the dibenzylbutandiol type
anti-tumor activity. On the other hand, some furofuran lig-
(+)-dihydroclusin, the tetrahydrofuran type (+)-burseran, and the
nans such as methyl piperitol (5) possess platelet activat-
ing factor (PAF) antagonist activity (Figure 2).6 Thus,
lignans possess a pharmacological array of properties
which evoked our interest in developing a general route to
access this valuable class of compounds.
dibenzocyclooctadiene type ( )-isostegane.
Key words: -amino nitriles, asymmetric synthesis, chiral auxilia-
ry, lignans, aldol reaction
Lignans constitute a class of natural products with a great
diversity in structure as can be exemplified with a possible
classification according to their carbon skeleton
(Figure 1).1
R
O
O
O
OCOCH3
O
O
H
O
CH3O
O
These compounds possess significant pharmacological
activities, especially antiviral and antitumor properties,
and have therefore been the target of extensive synthetic
research.2,3
O
CH3O
CH3O
OCH3
OCH3
1 R = OH, β-H podophyllotoxin
OCH3
3 steganacin
2 R = H, α-H isodeoxypodophyllotoxin
O
Ar1
Ar2
(OH)
(OH)
Ar
2 Ar1
Ar1
OCH3
O
O
O
O
O
OCH3
Ar1
O
O
O
Ar2
Ar2
O
dibenzyl-
butan(diol)es
furofurans
dibenzylbutyro-
lactones
tetrahydro-
furans
H
H
R1O
CH3O
OCH3
(OR3)
(OH)
(OH)
O
O
OCH3
(−)-4 burseran
O
O
O
5 methyl piperitol
O
RO
RO
O
Figure 2 Some pharmacologically active lignans.
Ar
Ar
O
R2O
dibenzocyclooctadienes
tetralins
naphthalenes
We have recently developed a highly efficient diastereo-
and enantioselective route via enantiopure -amino ni-
triles to 2,3-dibenzylated -butyrolactones 9, which are
very important building blocks in the synthesis of lignans
(Scheme 1).7 The synthesis commenced with an asym-
metric Strecker reaction using different aromatic alde-
hydes and the enantiomerically pure secondary amine 6 as
starting materials followed by a Michael reaction of lithi-
ated 7 to 5H-furan-2-one to give the 1,4-adducts 8 in good
Figure 1 Classification of lignans.
Podophyllotoxin (1), for example, has been under contin-
uous investigation owing to its significant anti-tumor ac-
Synthesis 2002, No. 4, 15 03 2002. Article Identifier:
1437-210X,E;2002,0,04,0515,0522,ftx,en;Z01502SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

516
D. Enders et al.
PAPER
H3C
O
CH3
CH3
CH3
O
O
O
Ar1
R
O
O
O
H3C
N
CN
O
N
H
6
Ar2
9
O
O
O
O
H3C
O
O
O
OH
de = 60 - > 98%,
ee > 96%
60 - 68%
Ar1CHO
H2O, HCl,
pH = 4-5,
KCN
O
Ar
9a-c
1. 2.0 equiv t-BuLi, THF, −78 °C,
Ar2CH2Br, −90 to 0 °C or
(ZnCl2), Ar2CHO, NH4Cl, H2O
8
59 - 91%
54 - 88%b
syn:anti (aldol) >96:4 - >99:1
ee > 98%
de > 98%
2. AgNO3, H2O, THF, 25°C
1. LDA, LiCl (2.2 equiv),
THF, −78 °C
2. −100 °C, ArCHO
3. NH4Cl, H2O
CH3
CH3
H3C
O
CH3
O
CH3
CH3
1. THF or Et2O,
LDA, −78 °C,
2. butenolide, −78 °C
3. NH4Cl, H2O
O
AgNO3,
THF/H2O, rt
O
O
O
H3C
Ar1
N
CN
H3C
N
CN
79 - 84%a
N
CN
H3C
O
O
*
O
Ar1
O
OH
7
8
O
O
Ar
aafter purification
bwhen Ar1= piperonyl
R = H or OH
de = 56 - 80% (94 - 98%)a
10a-c
syn:anti (aldol) = 87:13 - 93:7
Scheme 1
Ar = a: veratryl, b: piperonyl, c: 3,4,5-tri-CH3OC6H2
Scheme 2
yields and diastereoselectivities. Alkylation of 8 provided
the products 9 after cleavage of the auxiliary with excel-
lent induction (de 98%, ee = 96 97%), whereas the syn/
anti selectivity of the aldol addition (de = 60 75%) still
required some improvement.
22
lization provided ( )-methyl piperitol (5)10 {[ ]D
73.0
(c = 0.60, CHCl3), lit.11 [ ]D +73.6 (c = 0.35, CHCl3)},
22
22
( )-sesamin (13)12 {[ ]D
71.0 (c = 0.30, CHCl3), lit.13
22
[ ]D +68.7 (c = 0.40, CHCl3)} and ( )-aschantin (14)
Initial experiments to increase the selectivity of the aldol
reaction via transmetalation of the intermediate lithium
lactone enolate were met with moderate success: ZnBr2,
ZnI2, MgBr2, ClTi(OiPr)3 and BrTi(NEt2)3, for example,
did not improve stereocontrol, whereas ZnCl2 had a
slightly favorable effect. However, by using LiCl as addi-
tive the stereocontrol could now be increased. Best results
were obtained by using 2.2 equivalents of LiCl and by
adding the aldehyde at 100 °C. This resulted in a syn/anti
ratio of 87:13 93:7 where the syn/anti nomenclature re-
fers to the stereochemistry between the alcohol group and
the adjacent stereocenter (Scheme 2). Due to the instabil-
ity of the obtained alcohols 10a c, a purification of the
products was only possible after the cleavage of the aux-
iliary resulting in even higher ratios syn/anti (aldol) of
96:4 99:1. The enantiomeric excesses determined via 1H
NMR shift experiments using Pirkle-alcohol as chiral co-
solvent was found to be 98%.7,8
22
22
{[ ]D
64.0 (c = 0.55, CHCl3), lit.13 [ ]D +65.0
(c = 0.40, CHCl3)} in high optical purity (Scheme 3). To
the best of our knowledge, this constitutes the first synthe-
sis of aschantin and the first asymmetric synthesis of me-
thyl piperitol.
We were interested in extending this methodology to oth-
er lignans. The most plausible way to reach this goal is to
synthesize yatein (17), which is a springboard to other
classes of lignans, in an efficient way. A suitable starting
material for this is our previously synthesized virtually di-
astereo- and enantiopure trans-2,3-disubstituted -butyro-
lactone 15.7 Reduction of the ketone was accomplished
with sodium borohydride in methanol to give the alcohol
16 as a pair of epimers (83:17) in 80% yield. Catalytic
hydrogenolysis14 of 16 gave (+)-yatein (17)15 in very good
22
yield (88%) and optical purity {[ ]D +30.6 (c = 1.10,
22
CHCl3), lit.16b [ ]D
30.0 (c = 0.15, CHCl3)}. Having
opened a very efficient access to the tetrahydrofuran lig-
nan yatein (17), we decided to continue by synthesis of the
dibenzocyclooctadiene type compound, ( )-isostegane
(18). Modification of the oxidative coupling by
Planchenault et al.17 of 17 with Tl2O3 in the presence of
The aldol compounds 9a c were converted into natural
products following the procedure of Ogiku et al.9 Reduc-
tion of 9a c was performed with L-selectride at 78 °C to
give the diol lactones 11a c in good yield and high dia-
stereomeric purity. Performing the lithium aluminium hy-
dride reduction at 60 °C for 1 hour gave the tetraols 12a
c in moderate yield. Finally, mesylation of the primary hy-
droxyl groups with methanesulfonyl chloride in pyridine
followed by spontaneous intramolecular double cyc-
22
BF3 OEt2 in neat TFA gave ( )-isostegane (18)18 {[ ]D
18a
22
156.9 (c = 2.8, CHCl3), lit.
[ ]D +154.0 (c = 0.7,
CHCl3)} in very good yield (77%). This also constitutes a
formal total synthesis of the known anti-tumor lignan ste-
Synthesis 2002, No. 4, 515–522 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A General Approach to the Asymmetric Synthesis of Lignans
517
O
OH
O
O
O
Ar
O
O
O
O
O
O
NaBH4, MeOH
80%
H
H
O
O
O
OH
O
O
20 - 27%
O
O
O
Ar
9a-c
5, 13, 14
ds > 98%
ee > 98%
CH3O
OCH3
CH3O
OCH3
syn:anti (aldol) > 96:4 - > 99:1
ee > 98%
OCH3
OCH3
16
15
MsCl,
pyridine
49 - 54%
L-Selectride,
THF, −78 °C
70 - 84%
de > 98%, ee = 97%
H2, Pd/C
HClO4, EtOH 88%
4 atm, rt
OH
OH
O
O
O
O
O
OH
OH
OH
LiAlH4, THF
91%
LiAlH4, THF, 60 °C
55 - 61%
O
O
OH
Ar
OH
Ar
OH
O
O
O
O
O
11a-c
12a-c
ds > 98%
ds > 98%
CH3O
OCH3
CH3O
OCH3
OCH3
19 dihydroclusin
Ar = a: veratryl, b: piperonyl, c: 3,4,5-tri-CH3OC6H2
OCH3
17 yatein
Scheme 3
MeOH, HCl
reflux, 48 h
.
85 %
Tl2O3,BF3 OEt2,
TFA, 0 °C
77%
ganacin (3), as Koga and co-workers19 elegantly made this
transformation earlier. Furthermore, by changing condi-
tions of the oxidative coupling, access to tetralin lignans
can be obtained by the transformation of yatein to isode-
oxypodophyllotoxin (2).17,20 We were also interested in
accessing the dibenzylbutandiole and tetrahydrofuran lig-
nans and thus subjected yatein to reductive conditions
with lithium aluminium hydride to give (+)-dihydroclusin
O
O
O
O
O
O
O
CH3O
CH3O
OCH3
CH3O
H3CO
OCH3
(+)-4 burseran
18 isostegane
(19)21 {[ ]D22 +27.0 (c = 1.15, CHCl3), lit.22b [ ]D
22
27.13 (c = 0.24, CHCl3)} in excellent yield (91%). Re-
fluxing 19 in a methanolic solution containing HCl analo-
gous to Ward and co-workers23 afforded the anti-tumor
Scheme 4
22
lignan (+)-burseran (+)-(4)24 {[ ]D +37.8 (c = 2.0,
lution mass spectra were recorded on a Finnigan MAT 95 spectro-
1
22
CHCl3); lit.25,18a [ ]D
yield.
34.8 (c = 0.93, CHCl3)} in 85%
meter. IR spectra were taken on a Perkin Elmer FT/IR 1760. H
NMR (300 and 400 MHz) and 13C NMR (75 and 100 MHz) spectra
were recorded on Gemini 300 or Varian Inova 400 (CDCl3 as sol-
vent, TMS as internal standard) spectrometers.
In conclusion, we have increased the diastereoselectivity
of our previously reported aldol reaction by using LiCl as
additive. The obtained 2,3-disubstituted -butyrolactones
were successfully converted into a broad range of differ-
ent lignans. By using the other enantiomer of amine 6, one
can easily access both enantiomers of the lignans demon-
strating the high diversity and utility of this methodology.
2,3-Disubstituted -Butyrolactones 9a c; General Procedure 1
(GP1)
Anhyd LiCl (2.2 equiv) was put in a dried Schlenk-flask after which
diisopropyl amine (1.2 equiv) and anhyd THF (3 mL per mmol di-
isopropyl amine) were added. The flask was cooled to –78 °C and
n-BuLi (1.2 equiv, 1.6 M) was added dropwise. The soln was stirred
at 0 °C for 30 min. This mixture was added via a syringe pump to
another flask cooled to 78 °C containing the Michael adduct 8
(1 equiv) in anhyd THF (10 mL per mmol Michael adduct). After
90 min, the soln was cooled to 100 °C and the corresponding aro-
matic aldehyde (1.2 equiv) dissolved in anhyd THF (2 mL per mmol
aldehyde) was added very slowly via a syringe pump. After 20 min
at 100 °C the cooling bath was removed and the reaction was
quenched by adding quickly sat. NH4Cl soln under vigorous stir-
ring. The mixture was allowed to warm to r.t., H2O was added and
the organic phase was separated. The aq phase was extracted with
All moisture-sensitive reactions were carried out by using standard
Schlenk techniques unless stated otherwise. Solvents were dried
and purified by conventional methods prior to use. THF was freshly
distilled from Na-Pb alloy, CH2Cl2 from CaH2 under argon. Re-
agents of commercial quality were used from freshly opened con-
tainers or purified by common methods. n-BuLi (1.6 M in hexane)
was purchased from Merck, Darmstadt. Preparative column chro-
matography: Merck silica gel 60, particle size 0.040 0.063 mm
(230 240 mesh, flash). Analytical TLC: silica gel 60 F254 plates
from Merck, Darmstadt. Optical rotation values were measured on
a Perkin Elmer P241 polarimeter; solvents used were of Merck
UVASOL-quality. Microanalyses were obtained with a Heraeus
CHN-O-RAPID element analyzer. Mass spectra were acquired on a
Finnigan SSQ7000 (CI 100 eV; EI 70 eV) spectrometer. High reso-
Et2O (3
mL) and the combined organic layers were washed with
sat. NaCl soln, dried with MgSO4 and evaporated in vacuo. The
crude product was dissolved in THF (10 mL per mmol aldol prod-
uct) and the flask was covered with aluminium foil. AgNO3 (2 N, 4
equiv) was added and the mixture was stirred 15 min (TLC control)
after which Et2O (20 mL per mmol aldol product) was added and
Synthesis 2002, No. 4, 515–522 ISSN 0039-7881 © Thieme Stuttgart · New York

518
D. Enders et al.
PAPER
stirring was continued for an additional 30 min. The Ag-residues
were removed via filtration and washed with Et2O and H2O. After
OCH2O), 6.72 (d, 1 H, J = 8.1 Hz, arom. CH), 6.83 (d, 1 H, J = 8.4
Hz, arom. CH), 6.86 (s, 1 H, arom. CH), 6.89 (d, 1 H, J = 8.4 Hz,
arom. CH), 7.02 (d, 1 H, J = 1.7 Hz, arom. CH), 7.24 (dd, 1 H,
J = 1.7, 8.4 Hz, arom. CH).
partitioning, the aq phase was extracted with Et2O (3
mL). The
mL),
combined org. layers were washed with sat. NaCl soln (3
dried with MgSO4 and evaporated in vacuo. The crude product was
purified via column chromatography or recrystallization.
13C NMR (75 MHz, DMSO-d6): = 41.44 (CHCH2OC=O), 51.63
(CHCO2), 68.70 (CH2 OC=O), 69.84 (CHOH), 100.70, 102.03
(OCH2O), 106.15, 107.43, 107.60, 107.81, 118.56, 124.76 (arom.
CH), 129.56, 136.40, 146.08, 147.01, 147.65, 151.69 (arom. C),
176.02 (OC=O), 196.26 (C=O).
Lactone Diols 11a c; General Procedure 2 (GP2)
Alcohol 9a c (1 equiv) was dissolved in anhyd THF (16 mL per
mmol alcohol) and cooled to 78 °C. L-Selectride (1.3 equiv) was
added dropwise and after 30 min the cooling bath was removed. The
mixture was hydolysed with H2O and immediately partitioned be-
tween H2O and EtOAc. After removal of the aq phase, the organic
IR (KBr): 3469 (s, br, OH), 3072 (vw), 2984 (vw), 2902 (w), 2881
(m), 1754 (vs, C=Olactone), 1673 (vs, C=Oarylketone), 1605 (s), 1500
(vs), 1446 (vs), 1414 (m), 1386 (m), 1362 (m), 1255 (vs), 1194 (s),
1176 (s), 1134 (m), 1112 (m), 1094 (m), 1079 (m), 1038 (vs), 937
layer was washed with sat. NaCl soln (2
mL), dried with MgSO4
1
(s), 926 (s), 875 (m), 820 (m), 807 (m), 788 (m), 744 (w) cm .
and evaporated in vacuo. The crude product was purified via col-
umn chromatography.
MS (EI, 70 eV): m/z (%) = 384 (0.3) [M+ ], 234 (12), 151 (5), 150
(40), 149 (100), 121 (23), 91 (6), 65 (14), 63 (14), 62 (5).
Tetraols 12a c; General Procedure 3 (GP3)
Anal. Calcd for C20H16O8 (384.34): C, 62.50; H, 4.20. Found: C,
62.25; H, 4.17.
LiAlH4 (10 equiv) was suspended with anhyd THF (2 mL per mmol
LiAlH4) in a Schlenk-flask equipped with a condenser. The suspen-
sion was heated to 60 °C and diol 11a c (1 equiv) dissolved in an-
hyd THF (10 mL per mmol diol) was slowly injected via a syringe
pump. After 1 h at 60 °C the soln was allowed to cool to r.t., hydro-
lyzed with 10% NaOH soln and stirred for an additional 10 min. The
precipitate was removed via filtration and was extracted twice by
refluxing in THF. The combined filtrates were evaporated in vacuo.
The crude product was purified via column chromatography.
(3R,4S)-4-(1,3-Benzodioxol-5-ylcarbonyl)-3-[(R)-1-hydroxy-1-
(3,4,5-trimethoxyphenyl)methyl]tetrahydro-2-furanone (9c)
Compound 87 (1.020 g, 2.20 mmol) was subjected to the aldol reac-
tion conditions followed by the cleavage of the auxiliary according
to GP1. Work-up and column chromatography (Et2O pentane,
30:1) gave 9c (570 mg, 60% over two steps) as a colorless solid; mp
143 °C.
[ ]D22 +58.0 (c = 1.01, CHCl3).
Furofuran Lignans 5,13,14; General Procedure 4 (GP4)
To the tetraol 12a c dissolved in anhyd CH2Cl2 (10 mL per mmol
tetraol) was added at 0°C, pyridine (0.8 mL per mmol tetraol) and
MsCl (3 equiv). The reaction mixture was allowed to warm to r.t.
overnight. The mixture was washed with H2O, 10% soln of citric
syn:anti (aldol) = 87:13 (1H NMR); 98:2 (after column chroma-
tography, 1H NMR); ee 98% (determined with 1H NMR shift re-
agent: Pirkle-alcohol).
The analytical data are identical to those reported earlier.7
acid (2
mL), and finally with sat. NaCl soln. The organic layer
was dried with MgSO4 and evaporated in vacuo. The crude product
was purified via column chromatography.
(3R,4S)-4-[(R)-1-(1,3-Benzodioxol-5-yl)-1-hydroxymethyl]-3-
[(R)-1-(3,4-dimethoxyphenyl)-1-hydroxymethyl]tetrahydro-2-
furanone (11a)
Ketone 9a (550 mg, 1.37 mmol) was reduced with L-selectride
according to GP2. Work-up and column chromatography
(CH2C12 MeOH, 30:1) gave 11a (410 mg, 75%) as a colorless sol-
id; mp 165 °C.
(3R,4S)-4-(1,3-Benzodioxol-5-ylcarbonyl)-3-[(R)-1-(3,4-dimeth-
oxyphenyl)-1-hydroxymethyl]tetrahydro-2-furanone (9a)
Compound 87 (1.020 g, 2.20 mmol) was subjected to the aldol reac-
tion conditions followed by the cleavage of the auxiliary according
to GP1. Work-up and column chromatography (Et2O pentane,
10:1) gave 9a (600 mg, 68% over two steps) as a colorless solid; mp
133 °C.
[ ]D22 +20.7 (c = 0.95, acetone).
ds 98% (1H NMR).
[ ]D22 +62.0 (c = 0.99, CHCl3).
IR (KBr): 3500 (vs, br, OH), 3055 (w), 3005 (m), 2962 (m), 2941
(m), 2910 (m), 2836 (m), 1742 (vs, C=Olactone), 1640 (w), 1609 (w),
1595 (m), 1517 (vs), 1505 (vs), 1487 (s), 1469 (s), 1439 (s), 1414
(m), 1398 (m), 1307 (s), 1256 (vs), 1236 (vs), 1217 (vs), 1199 (vs),
1153 (m), 1135 (s), 1081 (s), 1028 (vs), 989 (m), 940 (m), 916 (m),
syn:anti (aldol) = 93:7 (1H NMR); 99:1 (after column chromatog-
raphy, 1H NMR); ee 98% (determined with 1H NMR shift reagent:
Pirkle-alcohol).
The analytical data are identical to those reported earlier.7
1
864 (m), 818 (m), 790 (m) cm .
1H NMR (300 MHz, CDC13): = 2.10 (d, 1 H, J = 2.7 Hz, OH),
2.76 (dddd, 1 H, J = 4.0, 4.0, 4.4, 8.4 Hz, CHCH2C = O), 2.77 (d, 1
H, J = 4.7 Hz, OH), 2.94 (dd, 1 H, J = 3.7, 4.4 Hz, CHCO2), 3.80 (s,
3 H, OCH3), 3.87 (s, 3 H, OCH3), 4.17 (dd, 1 H, J = 4.4, 9.0 Hz,
CHHOC=O), 4.29 (dd, 1 H, J = 8.4, 8.7 Hz, CHHOC=O), 4.62 (dd,
1 H, J = 4.0, 4.7 Hz, CHOH), 5.21 (dd, 1 H, J = 3.0, 5.0 Hz,
CHOH), 5.93 (d, 1 H, J = 1.7 Hz, OCHHO), 5.96 (d, 1 H, J = 1.7
Hz, OCHHO), 6.39 (d, 1 H, J = 1.4 Hz, ArH), 6.58 (dd, 1 H, J = 1.7,
8.4 Hz, ArH), 6.60 (d, 1 H, J = 1.7 Hz, ArH), 6.63 (d, 1 H, J = 8.1
Hz, ArH), 6.76 (d, 1 H, J = 8.4 Hz, ArH), 6.83 (dd, 1 H, J = 1.4, 8.4
Hz, ArH).
(3R,4S)-4-(1,3-Benzodioxol-5-ylcarbonyl)-3-[(R)-1-(1,3-benzo-
dioxol-5-yl)-1-hydroxymethyl]tetrahydro-2-furanone (9b)
Compound 87 (1.020 g, 2.20 mmol) was subjected to the aldol reac-
tion conditions followed by the cleavage of the auxiliary according
to GP1. Work-up and recrystallization from CH2Cl2 gave 9b (550
mg, 65% over two steps) as a colorless solid; mp 146 °C.
[ ]D22 +74.0 (c = 1.00, acetone).
syn:anti (aldol) = 88:12 (1H NMR); 96:4 (after recrystallization,
1
1H NMR); ee 98% (determined with H NMR shift reagent:
Pirkle-alcohol).
1H NMR (300 MHz, DMSO-d6): = 3.22 (dd, 1 H, J = 2.7, 6.0 Hz,
CHCO2), 4.10 (dd, 1 H, J = 5.7, 8.4 Hz, CHHOC=O), 4.38 (ddd, 1
H, J = 5.7, 6.0, 8.4 Hz, CHCH2OC=O), 4.57 (t, 1 H, J = 8.4 Hz,
CHHOC=O), 5.13 (m, br, 1 H, CHOH), 5.89 (s, 1 H, OCHHO), 5.93
(s, 1 H, OCHHO), 6.03 (d, br, 1 H, J = 3.7 Hz, OH), 6.11 (s, 2 H,
13C NMR (75 MHz, CDC13): = 42.59 (CHCH2C=O), 48.94
(CHCO2), 55.67, 55.76 (OCH3), 70.62 (CH2C=O), 73.16, 75.09
(CHOH), 101.37 (OCH2O), 105.80, 107.82, 108.53, 110.73,
117.61, 118.73 (ArH), 133.39, 134.74, 147.30, 147.91, 148.47,
148.85 (Ar), 178.61 (OC=O).
Synthesis 2002, No. 4, 515–522 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A General Approach to the Asymmetric Synthesis of Lignans
519
MS (EI, 70 eV): m/z (%) = 402 (0.3) [M+ ], 167 (14), 166 (100), 165
(52), 151 (27), 149 (10), 137 (7), 123 (8), 122 (5), 121 (5), 119 (6),
109 (6), 107 (5), 105 (6), 95 (30), 93 (8), 85 (5), 83 (6), 80 (5), 79
(15), 77 (24), 71 (6), 69 (7), 67 (9), 65 (12), 63 (7).
H, ArH), 6.35 (d, 1 H, J = 1.4 Hz, ArH), 6.50 (dd, 1 H, J = 1.4, 8.0
Hz, ArH), 6.54 (d, 1 H, J = 8.0 Hz, ArH).
13C NMR (100 MHz, CDC13): = 42.56 (CHCH2C=O), 48.82
(CHCO2), 56.00 (m-OCH3), 60.78 (p-OCH3), 71.26 (CH2C=O),
73.04, 74.73 (CHOH), 101.40 (OCH2O), 102.45, 105.68, 107.65,
118.50 (Ar), 134.85, 136.83, 136.92, 147.07, 147.78, 152.98 (Ar),
179.31 (OC=O).
Anal. Calcd for C21H22O8 (402.40): C, 62.68; H, 5.51. Found: C,
62.30; H, 5.63.
(3R,4S)-3,4-Di[(R)-1-(1,3-benzodioxol-5-yl)-1-hydroxymeth-
yl]tetrahydro-2-furanone (11b)
Ketone 9b (480 mg, 1.25 mmol) was reduced with L-Selectride ac-
cording to GP2. Work-up and column chromatography (CH2C12
MeOH, 30:1) gave 11b (340 mg, 70%) as a colorless solid; mp 186
°C.
MS (EI, 70 eV): m/z (%) = 432 (4) [M+ ], 236 (10), 219 (7), 198 (5),
197 (29), 196 (100), 195 (6), 182 (6), 181 (53), 169 (8), 153 (9), 152
(6), 151 (33), 150 (10), 149 (17), 138 (7), 135 (6), 125 (26), 123
(11), 121 (7), 111 (5), 110 (18), 97 (6), 95 (12), 93 (31), 91 (5), 85
(6), 83 (6), 82 (5), 81 (6), 79 (6), 77 (10), 71 (6), 70 (6), 69 (8), 67
(7), 66 (5), 65 (14), 63 (5), 57 (14), 56 (5), 55 (13), 53 (7), 51 (7),
45 (5).
[ ]D22 +26.6 (c = 1.01, acetone).
ds 98% (1H NMR).
Anal. Calcd for C22H24O9 (432.43): C, 61.11; H, 5.59. Found: C,
61.15; H, 5.97.
IR (KBr): 3559 (vs, OH), 3414 (vs, br, OH), 3067 (w), 2969 (m),
2903 (s), 1753 (vs, C=Olactone), 1501 (vs), 1443 (s), 1395 (m), 1318
(w), 1257 (vs), 1234 (s), 1192 (m), 1109 (w), 1093 (w), 1076 (m),
1068 (m), 1035 (s), 993 (w), 938 (m), 906 (w), 866 (vw), 810 (w),
(1R,2S,3S,4R)-1-(1,3-Benzodioxol-5-yl)-4-(3,4-dimethoxyphen-
yl)-2,3-di(hydroxymethyl)butan-1,4-diol (12a)
Diol 11a (241 mg, 0.60 mmol) was reduced with LiAlH4 (228 mg,
6.00 mmol) according to GP3. Purification via column chromatog-
raphy (CH2Cl2 MeOH,10:1) gave 12a (135 mg, 55%) as a colorless
solid; mp 181 °C.
1
785 (w), 661 (vw) cm .
1H NMR (400 MHz, DMSO-d6): = 2.50 (m, br, 1 H, CHCO2),
2.54 (m, br, 1 H, CHCH2C=O), 4.23 (dd, 1 H, J = 1.9, 8.3 Hz,
CHHOC=O), 4.35 (dd, 1 H, J = 8.2, 8.3 Hz, CHHOC=O), 4.56 (m,
br, 1 H, CHOH), 4.91 (m, br., 1 H, CHOH), 5.49 (d, 1 H, J = 4.1 Hz,
OH), 5.67 (d, 1 H, J = 3.8 Hz, OH), 5.90 (d, 1 H, J = 1.1 Hz,
OCHHO), 5.91 (d, 1 H, J = 1.1 Hz, OCHHO), 5.93 (d, 1 H, J = 1. 1
Hz, OCHHO), 5.95 (d, 1 H, J = 1. 1 Hz, OCHHO), 6.36 (d, 1 H,
J = 1.1 Hz, ArH), 6.43 (s, 1 H, ArH), 6.44 (d, 1 H, J = 8.2 Hz, ArH),
6.49 (dd, 1 H, J = 1.1, 8.0 Hz, ArH), 6.57 (d, 1 H, J = 8.0 Hz, ArH),
6.59 (d, 1 H, J = 8.0 Hz, ArH).
[ ]D22 +37.0 (c = 1.00, acetone).
IR (KBr): 3414 (s, br, OH), 3071 (w), 3007 (m), 2959 (m), 2941
(m), 2892 (m), 2860 (s), 1518 (vs), 1491 (s), 1465 (s), 1438 (m),
1413 (m), 1381 (w), 1365 (w), 1323 (m), 1257 (vs), 1236 (vs), 1208
(m), 1157 (m), 1138 (s), 1105 (w), 1066 (s), 1026 (vs), 991 (w), 927
(m), 892 (m), 874 (w), 857 (w), 819 (m), 786 (w), 764 (w), 676 (m),
591 (w) cm–l.
13C NMR (100 MHz, DMSO-d6): = 41.19 (CHCH2C=O), 47.65
(CHCO2), 71.36 (CHOH), 71.72 (CH2OC=O), 72.62 (CHOH),
100.57, 100.64 (OCH2O), 105.40, 105.48, 106.94, 107.03, 117.90,
117.98 (Ar), 136.17, 136.26, 145.40, 145.55, 146.43, 146.50 (Ar),
178.53 (OC=O).
MS (EI, 70 eV): m/z (%) = 386 (1) [M+ ], 236 (23), 152 (9), 151
(84), 150 (77), 149 (100), 132 (6), 131 (6), 123 (18), 122(6), 121
(35), 119 (7), 103 (9), 93 (47), 91 (14), 77 (11), 66 (6), 65(47), 64
(9), 63 (42), 62 (17), 61 (10), 58 (5), 57 (13), 55 (6), 53 (10), 51 (11),
50 (9).
1H NMR (400 MHz, DMSO-d6): = 1.94 (m, 1 H, CHCH2OH),
1.99 (m, 1 H, CHCH2OH), 3.52 (m, 4 H, CH2OH), 3.60 (s, 3 H,
OCH3), 3.72 (s, 3 H, OCH3), 4.64 (dd, 1 H, J = 4.7, 5.2 Hz, CHOH),
4.66 (dd, 1 H, J = 4.4, 5.0 Hz, CHOH), 5.05 (t, 1 H, J = 4.4 Hz,
CH2OH), 5.08 (t, 1 H, J = 4.4 Hz, CH2OH), 5.38 (d, 1 H, J = 5.0 Hz,
CHOH), 5.42 (d, 1 H, J = 5.2 Hz, CHOH), 5.91 (d, 1 H, J = 1.1 Hz,
OCHHO), 5.95 (d, 1 H, J = 1.4 Hz, OCHHO), 6.33 (d, 1 H, J = 1.4
Hz, ArH), 6.43 (d, 1 H, J = 1.7 Hz, ArH), 6.51 (dd, 1 H, J = 1.1, 8.2
Hz, ArH), 6.53 (dd, 1 H, J = 1.7, 8.5 Hz, ArH), 6.54 (d, 1 H, J = 8.2
Hz, ArH), 6.75 (d, J = 8.5 Hz, 1 H, ArH).
13C NMR (100 MHz, DMSO-d6): = 44.19, 44.33 (CHCH2OH),
54.77, 55.24 (OCH3), 59.32, 59.39 (CH2OH), 71.10, 71.18
(CHOH), 100.46 (OCH2O), 105.91, 106.81, 109.07, 110.57,
117.61, 118.47 (Ar), 137.21, 138.81, 145.10, 146.46, 146.94,
147.88 (Ar).
Anal. Calcd for C20H18O8 (386.36): C, 62.18; H, 4.70. Found: C,
62.67; H, 5.07.
(3R,4S)-4-[(R)-1-(1,3-Benzodioxol-5-yl)-1-hydroxymethyl]-3-
[(R)-1-hydroxy-1-(3,4,5-trimethoxyphenyl)methyl]tetrahydro-
2-furanone (11c)
Ketone 9c (486 mg, 1.13 mmol) was reduced with L-Selectride ac-
cording to GP2. Work-up and column chromatography (CH2C12
MeOH, 30:1) gave 11c (410 mg, 84%) as a colorless solid; mp 174
°C.
MS (EI, 70 eV): m/z (%) = 406 (8) [M+ ], 238 (16), 222 (38), 210
(7), 207 (8), 194 (7), 192 (6), 191 (11), 189 (17), 177 (6), 174 (17),
168 (9), 167 (50), 165 (5), 151 (100), 150 (27), 139 (31), 135 (7),
131 (5), 123 (16), 121 (6), 108 (9), 97 (6), 95 (5), 93 (23), 91 (6), 85
(5), 81 (5), 79 (5), 77 (6), 69 (5), 65 (10).
[ ]D22 +18.4 (c = 1.00, acetone).
ds 98% (1H NMR).
Anal. Calcd for C21H26O8 (406.43): C, 62.06; H, 6.45. Found: C,
62.18; H, 6.58.
IR (KBr): 3478 (s, br, OH), 2971 (m), 2941 (m), 2907 (w), 2840
(w,), 1758 (vs, C=Olactone), 1595 (s), 1506 (vs), 1492 (s), 1461 (s),
1420 (s), 1389 (m), 1334 (m), 1238 (vs), 1191 (s), 1127 (vs), 1080
(1R,2S,3S,4R)-1,4-Di(1,3-benzodioxol-5-yl)-2,3-di(hydroxy-
methyl)butan-1,4-diol (12b)
Diol 11b (170 mg, 0.44 mmol) was reduced with LiAlH4 (167 mg,
4.40 mmol) according to GP3. Purification via column chromato-
graphy (CH2Cl2 MeOH, 10:1) gave 12b (100 mg, 58%) as a color-
less solid; mp 208 °C.
1
(s), 1035 (vs), 926 (m) cm .
1H NMR (400 MHz, CDC13): = 2.72 (dddd, 1 H, J = 3.6, 3.8, 4.1,
8.2 Hz, CHCH2C=O), 2.84 (dd, 1 H, J = 3.6, 3.8 Hz, CHCO2), 3.16
(d, 1 H, J = 3.3 Hz, OH), 3.65 (d, 1 H, J = 5.2 Hz, OH), 3.76 (s, 9
H, OCH3), 4.22 (dd, 1 H, J = 3.8, 8.8 Hz, CHHOC=O), 4.36 (dd, 1
H, J = 8.2, 8.8 Hz, CHHOC=O), 4.61 (dd, 1 H, J = 3.6, 3.8 Hz,
CHOH), 5.11 (dd, 1 H, J = 3.8, 4.1 Hz, CHOH), 5.89 (d, 1 H,
J = 1.4 Hz, OCHHO), 5.94 (d, 1 H, J = 1.6 Hz, OCHHO), 6.34 (s, 2
[ ]D22 +26.0 (c = 0.98, MeOH).
IR (KBr): 3228 (vs, br, OH), 2991 (m), 2911 (s), 2888 (s), 1502 (vs),
1492 (vs), 1440 (vs), 1372 (m), 1334 (m), 1314 (m), 1078 (s), 1038
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520
D. Enders et al.
PAPER
(vs), 992 (m), 936 (vs), 860 (w), 814 (s), 787 (m), 770 (m), 734 (w),
721 (w), 677 (w), 612 (m), 565 (w), 531 (vw) cm–1.
2 H, CH2CH), 5.00 (d, 1 H, J = 7.7 Hz, CHOCH2), 5.02 (d, 1 H,
J = 8.0 Hz, CHOCH2), 5.97 (s, 2 H, OCH2O), 6.78 6.98 (m, 6 H,
ArH).
13C NMR (100 MHz, CDCl3): = 49.74, 49.89 (CHCH2O), 55.99,
56.03 (OCH3), 67.24, 67.33 (CH2CH), 81.92, 82.04 (CHOCH2),
101.24 (OCH2O), 106.40, 108.36, 109.17, 111.17, 118.55, 119.82
(Ar), 132.54, 134.29, 147.65, 148.24, 149.09, 149.42 (Ar).
1H NMR (400 MHz, DMSO-d6): = 1.94 (m, 2 H, CHCH2OH),
3.51 (m, 4 H, CH2OH), 4.65 (dd, 2 H, J = 3.9, 4.7 Hz, CHOH), 5.04
(m, 2 H, CH2OH), 5.40 (d, 2 H, J = 4.7 Hz, CHOH), 5.93 (s, 2 H,
OCH2O) 5.94 (s, 2 H, OCH2O), 6.43 (s, 2 H, ArH), 6.49 (d, 2 H,
J = 8.0 Hz, ArH) 6.66 (d, 2 H, J = 8.0 Hz, ArH).
13C NMR (100 MHz, DMSO-d6): = 44.25 (CHCH2OH), 59.30
(CH2OH), 71.03 (CHOH), 100.42 (OCH2O), 106.01, 106.95,
118.56 (arom. CH), 138.90, 145.14, 146.44 (arom. C).
HRMS: m/z calcd for C21H22O6 (M+), 370.1416; found, 370.1417.
The rest of the analytical data are in agreement with those previous-
ly reported.9,11,26
MS (EI, 70 eV): m/z (%) = 390 (6), 372 (13), 354 (11), 324 (5), 294
(11), 255 (10), 222 (28), 204 (20), 194 (11), 191 (14), 178 (9), 176
(8), 175 (7), 174 (36), 173 (21), 161 (12), 152 (12), 151 (100), 150
(41), 149 (50), 148 (8), 144 (7), 143 (9), 135 (24), 131 (11), 123
(13), 122 (7), 121 (13), 116 (6), 115 (10), 103 (7), 93 (36), 91 (6),
77 (7), 65 (22), 63 (6).
( )-Sesamin (13)
Tetraol 12b (80 mg, 0.20 mmol) was treated according to GP4 with
methanesulfonyl chloride (69 mg, 0.60 mmol) and pyridine (0.16
mL). Work-up and column chromatography (Et2O pentane, 9:1)
gave 13 (35 mg, 49%) as a colorless solid; mp 122 °C.
22
13
Anal. Calcd for C20H22O8 (390.39): C, 61.53; H, 5.68. Found: C,
61.28; H, 5.90.
[ ]D
CHCl3).
71.0 (c = 0.30, CHCl3), lit.
[ ]22 D = +68.7 (c = 0.40,
IR (KBr): 2973 (w), 2882 (m), 1610 (w), 1503 (vs), 1488 (vs), 1444
(vs), 1382 (m), 1315 (m), 1245 (vs), 1190 (m), 1101 (m), 1038 (vs),
925 (s), 861 (w), 809 (m), 788 (m), 731 (m), 716 (m) cm .
(1R,2S,3S,4R)-1-(1,3-Benzodioxol-5-yl)-2,3-di(hydroxymethyl)-
4-(3,4,5-trimethoxyphenyl)butan-1,4-diol (12c)
Diol 11c (240 mg, 0.55 mmol) was reduced with LiAlH4 (209 mg,
5.50 mmol) according to GP3. Purification via column chromatog-
raphy (CH2Cl2 MeOH, 10:1) gave 12c (145 mg, 61%) as a color-
less solid; mp 174 °C.
1
1H NMR (300 MHz, CDCl3): = 2.52 (m, 2 H, CHCH2O), 3.31 (dd,
2 H, J = 7.1, 9.3 Hz, CH2CH), 3.49 (dd, 2 H, J = 7.1, 9.1 Hz,
CH2CH), 4.33 (d, 2 H, J = 9.3 Hz, CHOCH2), 5.97 (s, 4 H, OCH2O),
6.75 (s, 2 H, ArH), 6.76 (s, 2 H, ArH), 6.87 (s, 2 H, ArH).
13C NMR (75 MHz, CDC13): = 52.47 (CHCH2O), 71.73
(CH2°CH), 76.74 (CHOCH2), 101.14 (OCH2O), 106.80, 108.09,
120.29 (Ar), 136.85, 147.44, 147.99 (Ar).
[ ]D22 +45.0 (c = 1.01, MeOH).
IR (KBr): 3221 (vs, br, OH), 2943 (s), 2895 (s), 2834 (m), 1596 (s),
1506 (vs), 1491 (s), 1452 (vs), 1417 (m), 1331 (m), 1256 (s), 1233
(s), 1130 (vs), 1086 (m), 1071 (m), 1038 (vs), 1006 (s), 931 (m), 838
(vw), 822 (w), 812 (m), 782 (w), 716 (m), 666 (w), 644 (w), 552
(vw) cm–1.
1H NMR (400 MHz, DMSO-d6): = 1.96 (m, 2 H, CHCH2OH),
3.51 (m, 2 H, CH2OH), 3.58 (m, 2 H, CH2OH), 3.63 (s, 3 H, p-
OCH3), 3.67 (s, 6 H, m-OCH3), 4.67 (m, 2 H, CHOH), 5.06 (t, 1 H,
J = 4.7 Hz, CH2OH), 5.07 (t, 1 H, J = 4.4 Hz, CH2OH), 5.42 (d, 1
H, J = 5.2 Hz, CHOH), 5.44 (d, 1 H, J = 5.0 Hz, CHOH), 5.91 (s, 1
H, OCHHO), 5.94 (s, 1 H, OCHHO), 6.28 (s, 2 H, ArH), 6.42 (s, 1
H, ArH), 6.46 (d, 1 H, J = 8.0 Hz, ArH), 6.62 (d, 1 H, J = 8.0 Hz,
ArH).
HRMS: m/z calcd for C20H18O6 (M+), 354.1103; found, 354.1101.
The rest of the analytical data are in agreement with those previous-
ly reported.26
( )-Aschantin (14)
Tetraol 12c (144 mg, 0.33 mmol) was treated according to GP4 with
methanesulfonyl chloride (113 mg, 0.99 mmol) and pyridine (0.27
mL). Work-up and column chromatography (Et2O) gave 14 (70 mg,
53%) as a colorless solid; mp 122 °C.
22
13
22
[ ]D
CHCl3).
64.0 (c = 0.55, CHCl3), lit.
[ ]D +65.0 (c = 0.40,
13C NMR (100 MHz, DMSO-d6): = 44.31, 44.36 (CHCH2OH),
55.39 (m-OCH3), 59.32, 59.37 (CH2OH), 59.76 (p-OCH3), 71.10,
71.42 (CHOH), 100.46 (OCH2O), 102.83, 105.95, 106.90, 118.47
(Ar), 135.48, 138.91, 140.56, 145.03, 146.42, 151.97 (Ar).
IR (KBr): 2938 (m), 2882 (m), 1593 (m), 1505 (s), 1488 (s), 1462
(s), 1422 (m), 1329 (m), 1242 (vs), 1127 (vs), 1038 (vs), 1008 (m),
1
929 (m), 815 (m), 788 (m), 683 (m) cm .
MS (EI, 70 eV): m/z (%) = 436 (14) [M+ ], 418 (36), 400 (26), 370
(12), 340 (10), 339 (14), 308 (10), 301 (13), 268 (12), 250 (10), 237
(10), 224 (32), 222 (32), 220 (13), 219 (18), 207 (15), 204 (23), 198
(27), 197 (100), 196 (31), 195 (16), 191 (22), 189 (18), 188 (10),
182 (11), 181 (27), 174 (49), 173 (21), 169 (65), 161 (11), 154 (25),
153 (10), 152 (14), 151 (81), 150 (28), 149 (29), 139 (12), 138 (26),
135 (23), 131 (10), 123 (12), 121 (10), 93 (27), 91 (7), 77 (10), 65
(17), 55 (10).
1H NMR (300 MHz, CDCl3): = 2.58 (m, 2 H, CHCH2O), 3.35 (dd,
1 H, J = 7.1, 9.3 Hz, CHHOCH), 3.40 (dd, 1 H, J = 7.1, 9.4 Hz,
CHHOCH), 3.55 (dd, 1 H, J = 7.7, 9.3 Hz, CHHOCH), 3.56 (dd, 1
H, J = 7.7, 9.3 Hz, CHHOCH), 3.84 (s, 3 H, p-OCH3), 3.87 (s, 6 H,
m-OCH3), 4.40 (d, 1 H, J = 7.4 Hz, CHOCH2), 4.43 (d, 1 H, J = 7.1
Hz, CHOCH2), 5.97 (s, 2 H, OCH2O), 6.57 (s, 2 H, ArH), 6.76 (d, 1
H, J = 7.7 Hz, ArH), 6.80 (dd, 1 H, J = 1.4, 8.0 Hz, ArH), 6.90 (d, 1
H, J = 1.0 Hz, ArH).
13C NMR (75 MHz, CDC13): = 52.44, 52.56 (CHCH2O), 56.15
(m-OCH3), 60.85 (p-OCH3), 71.73 (CH2CH), 76.86, 77.35
(CHOCH2), 101.19 (OCH2O), 103.46, 106.76, 108.15, 120.29 (Ar),
136.76, 137.68, 138.51, 147.54, 148.07, 153.35 (Ar).
Anal. Calcd for C22H28O9 (436.46): C, 60.54; H, 6.47. Found: C,
60.95; H, 6.48.
( )-Methyl Piperitol (5)
Tetraol 12a (130 mg, 0.32 mmol) was treated according to GP4 with
methanesulfonyl chloride (110 mg, 0.96 mmol) and pyridine (0.26
mL). Work-up and column chromatography (Et2O MeOH, 70:1)
gave 5 (65 mg, 54%) as a colorless solid; mp 74°C.
HRMS: m/z calcd for C22H24O7 (M+), 400.1522; found, 400.1523.
The rest of the analytical data are in agreement with those previous-
ly reported.26
22
11
22
[ ]D
CHCl3).
73.0 (c = 0.60, CHCl3), lit.
[ ]D +73.6° (c = 0.35,
(3S,4S)-4-[(R)-1-(1,3-Benzodioxol-5-yl)-1-hydroxymethyl]-3-
(3,4,5-trimethoxybenzyl)tetrahydro-2-furanone (16)
1H NMR (400 MHz, CDCl3): = 2.60 (m, 2 H, CHCH2O), 3.89 (s,
3 H, OCH3), 3.92 (s, 3 H, OCH3), 4.31 (m, 2 H, CH2CH), 4.41 (m,
Ketone 157 (307.2 mg, 0.74 mmol) was dissolved in MeOH (30 mL)
after which NaBH4 (90 mg, 2.34 mmol) was added. After 2 h (TLC
Synthesis 2002, No. 4, 515–522 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A General Approach to the Asymmetric Synthesis of Lignans
521
control), the reaction mixture was partitioned with CH2Cl2 and H2O.
The aq phase was extracted with CH2Cl2 (3 20 mL). The com-
bined organic layers were dried with MgSO4 and evaporated in vac-
uo. The crude product was purified via column chromatography
(Et2O pentane, 1:1 to 3:1) to give 16 (248.4 mg, 80%) as a mixture
of diastereomers (83:17). For analytical purposes a small sample
was purified via preparative HPLC to give the major diastereomer
( -alcohol) in pure form; mp 141 °C.
(1.5 mL). The reaction was quenched after 10 s by adding sat. aq
NaHCO3. The aq layer was extracted with CH2Cl2 (3 10 mL) after
which the combined organic layers were dried with MgSO4 and
evaporated in vacuo. The crude product was purified via column
chromatography (Et2O pentane, 1:1) to give 18 (69 mg, 77%) as a
colorless solid; mp 171 2 °C.
22
18a
22
[ ]D
CHCl3).
156.9 (c = 2.8, CHCl3); lit.
[ ]D +154.0 (c = 0.7,
[ ]D22 +1.1 (c = 0.93, acetone).
IR (KBr): 2931 (m), 1778 (vs, C=Olactone), 1595 (m), 1484 (vs), 1455
1
IR (KBr): 3471 (m, br, OH), 2939 (m), 2839 (w), 1763 (vs,
C=Olactone), 1592 (s), 1507 (s), 1490 (s), 1460 (s), 1423 (s), 1385
(w), 1325 (m), 1242 (vs), 1187 (s), 1127 (vs), 1036 (s), 1008 (s), 928
(s), 1403 (s), 1224 (vs), 1105 (vs), 1038 (vs), 997 (s) cm .
1H NMR (400 MHz, CDCl3): = 2.00 2.17 (m, 2 H, CH), 2.22 (dd,
1 H, J = 9.3, 13.6 Hz, CHHCHCO2), 2.32 (dd, 1 H, J = 9.6, 13.2 Hz,
CHHCHCO2), 2.57 (d, 1 H, J = 12.9 Hz, CHHCH2CO2), 3.06 (d, 1
H, J = 13.2 Hz, CHHCH2CO2), 3.50 (s, 1 H, OCH3), 3.70 (dd, 1 H,
J = 8.5, 11.0 Hz, CHHOC=O), 3.81 (s, 3 H, OCH3), 3.82 (s, 3 H,
OCH3), 4.29 (dd, 1 H, J = 6.6, 8.2 Hz, CHHOC=O), 5.90 (d, 1 H,
J = 1.3 Hz, OCHHO), 5.93 (d, 1 H, J = 1.3 Hz, OCHHO), 6.55 (s, 1
H, ArH), 6.56 (s, 1 H, ArH), 6.63 (s, 1 H, ArH).
13C NMR (75 MHz, CDCl3): = 32.55 (CH2CHCO2), 34.39
(CH2CHCH2C=O), 47.27 (CHCO2), 50.33 (CHCH2C=O), 56.30
(OCH3), 61.07 (OCH3), 61.23 (OCH3), 70.31 (CH2C=O), 101.46
(OCH2O), 107.74, 109.05, 112.02 (Ar), 126.70, 128.58, 132.74,
136.33, 146.16, 147.93, 152.14, 153.60 (Ar), 176.83 (OC=O).
1
(m), 815 (w), 783 (w), 738 (m), 672 (m) cm .
1H NMR (400 MHz, CDCl3): = 2.00 (d, 1 H, J = 2.8 Hz, OH), 2.63
(ddd, 1 H, J = 7.1, 7.2, 7.4 Hz, CHCO2), 2.95 (m, 2 H, CHHCHCO2,
CHCH2C = O), 3.06 (m, 1 H, CHHCHCO2), 3.83 (s, 9 H, OCH3),
3.95 (d, 2 H, J = 7.7 Hz, CH2C = O), 4.63 (dd, 1 H, J = 2.5, 6.9 Hz,
CHOH), 5.97 (d, 1 H, J = 1.4 Hz, OCHHO), 5.98 (d, 1 H, J = 1.4
Hz, OCHHO), 6.39 (s, 2 H, ArH), 6.73 (m, 3 H, ArH).
13C NMR (100 MHz, CDCl3): = 35.59 (CH2CHCO2), 43.69
(CHCO2), 45.02 (CHCH2C=O), 56.09 (m-OCH3), 60.85 (p-OCH3),
68.36 (CH2C=O), 75.34 (CHOH), 101.38 (OCH2O), 106.17,
106.74, 108.23, 119.29 (Ar), 133.28, 135.46, 147.65, 148.19,
153.11 (Ar), 179.04 (OC=O).
MS (EI, 70 eV): m/z (%) = 399 (24) [M+ + 1], 398 (100) [M+ ].
HRMS: m/z calcd for C22H22O7 (M+), 398.13655; found, 398.13663.
MS (EI, 70 eV): m/z (%) = 417 (26) [M+ +1], 416 (100) [M+ ], 238
(5), 221 (7), 183 (5), 182 (40), 181 (80), 177 (6), 169 (6), 168 (6),
167 (10), 161 (5), 152 (5), 151 (38), 149 (9), 148 (8), 135 (6), 131
(8), 123 (5), 93 (17), 65 (12).
(+)-Dihydroclusin (19)
To a suspension of LiAlH4 (80 mg, 2.1 mmol) in anhyd THF was
added at 0 °C (+)-yatein (17) (105 mg, 0.26 mmol) dissolved in an-
hyd THF (3 mL). The ice-bath was removed and the mixture stirred
for 3 h at r.t. EtOAc was added dropwise after which sat. NH4Cl (10
mL) and H2O (5 mL) were added. The mixture was filtered and the
filtrate was extracted with EtOAc (3 15 mL). The combined or-
ganic layers were dried with MgSO4 and evaporated in vacuo. The
crude product was purified via column chromatography (Et2O) to
give 19 (96 mg, 91%) as a colorless solid; mp. 98 100 °C.
Anal. Calcd for C22H28O9 (416.43): C, 63.45; H, 5.81. Found: C,
63.09; H, 5.84.
(+)-Yatein (17)
The epimeric mixture of alcohol 16 (200 mg, 0.48 mmol) was dis-
solved in anhyd EtOH (30 mL) and two drops of aq HClO4 was add-
ed. The mixture was hydrogenated using 10% Pd/C (60 mg) as
catalyst at 4 atm. After 16 h, the soln was neutralized with solid
Na2CO3 and the catalyst was filtered off. The solvent was evaporat-
ed in vacuo and the crude product was purified via column chroma-
tography (Et2O pentane, 1:1) to give 17 (170 mg, 88%) as a
colorless oil.
22
22b
22
[ ]D +27.0 (c = 1.15, CHCl3); lit.
[ ]D
27.13 (c = 0.24,
CHCl3).
IR (KBr): 3248 (m), 2938 (m), 2892 (m), 1591 (s), 1512 (s), 1486
(vs), 1458 (s), 1433 (s), 1241 (vs), 1130 (vs), 1034 (s), 1005 (vs),
22
16b
22
[ ]D +30.6 (c = 1.10, CHCl3); lit.
[ ]D
30.0 (c = 0.15,
1
925 (m), 908 (m), 815 (m) cm .
CHCl3).
1H NMR (400 MHz, CDCl3): = 1.77 1.85 (m, 2 H, CH), 2.58
(ddd, 2 H, J = 1.9, 6.3, 8.5 Hz, ArCH2), 2.68 (t, 1 H, J = 8 Hz,
ArCH2), 2.71 (t, 1 H, J = 7.7 Hz, ArCH2), 2.98 (br s, 2 H, OH), 3.48
(dd, 2 H, J = 3.9, 11.3 Hz, CH2OH), 3.75 (s, 6 H, OCH3), 3.76 (s, 3
H, OCH3), 3.74 3.77 (m, 2 H, CH2OH), 5.85 (s, 2 H, OCH2O), 6.29
(s, 2 H, ArH), 6.53 (dd, 1 H, J = 1.6, 8.0 Hz, ArH), 6.57 (d, 1 H,
J = 1.4 Hz, ArH), 6.64 (d, 1 H, J = 8.0 Hz, ArH).
13C NMR (75 MHz, CDCl3): = 36.16 (ArCH2), 36.86 (ArCH2),
43.96 (ArCH2CH), 44.33 (ArCH2CH), 56.31 (m-OCH3), 60.56
(CH2OH), 61.15 (p-OCH3), 101.08 (OCH2O), 103.49, 106.11,
108.34, 109.56, 122.13 (Ar), 134.58, 136.36, 136.66, 145.98,
147.84, 153.30 (Ar).
IR (KBr): 3015 (m), 2938 (m), 2840 (m), 1767 (vs, C=Olactone), 1591
1
(s), 1504 (s), 1490 (s), 1244 (vs), 1188 (vs), 755 (vs) cm .
1H NMR (300 MHz, CDCl3): = 2.46 2.64 (m, 4 H, CH2), 2.88
2.94 (m, 2 H, CH), 3.06 (m, 1 H, CHHCHCO2), 3.83 (s, 9 H, OCH3),
3.88 (dd, 1 H, J = 7.4, 9.0 Hz, CHHOC=O), 4.18 (dd, 1 H, J = 7.2,
9.3 Hz, CHHOC=O), 5.94 (dd, 2 H, J = 1.4, 3 Hz, OCH2O), 6.36 (s,
2 H, ArH), 6.46 6.49 (m, 2 H, ArH), 6.69 (dd, 1 H, J = 1.0, 6.9 Hz,
ArH).
13C NMR (75 MHz, CDCl3): = 35.23 (CH2CHCO2), 38.33
(CH2CHCH2C=O), 41.01 (CHCH2C=O), 46.44 (CHCO2), 56.09
(m-OCH3), 60.88 (p-OCH3), 71.20 (CH2C=O), 101.10 (OCH2O),
106.16, 108.31, 108.77, 121.54 (Ar), 131.53, 133.34, 136.80,
146.40, 147.92, 153.24 (Ar), 178.56 (OC=O).
MS (EI, 70 eV): m/z (%) = 405 (20) [M+ + 1], 404 (100) [M+ ], 209
(6), 183 (8), 182 (75), 181 (80), 167 (10), 151 (12), 136 (10), 135
(47), 77 (7).
MS (EI, 70 eV): m/z (%) = 401 (22) [M+ + 1], 400 (100) [M+ ], 182
(23), 181 (49), 151 (5), 136 (5), 135 (19), 77 (5).
HRMS: m/z calcd for C22H24O7 (M+), 400.15220; found, 400.15223.
HRMS: m/z calcd for C22H28O7 (M+), 404.18350; found, 404.18354.
(+)-Burseran (4)
( )-Isostegane (18)
(+)-Dihydroclusin (19) (52 mg, 0.13 mmol) was dissolved in MeOH
(30 mL) and 32% HCl (1 mL) was added. The soln was refluxed for
48 h after which the solvent was evaporated. The residue was neu-
tralized with sat. NaHCO3 and the aq phase was extracted with
(+)-Yatein (17) (90 mg, 0.22 mmol) dissolved in trifluoroacteic acid
(TFA; 1 mL) was added at 0 °C rapidly to a soln containing Tl2O3
(283 mg, 0.62 mmol) and BF3 OEt2 (0.06 mL, 0.5 mmol) in TFA
Synthesis 2002, No. 4, 515–522 ISSN 0039-7881 © Thieme Stuttgart · New York

522
D. Enders et al.
PAPER
(6) Pan, J.-X.; Hensens, O. D.; Zink, D. L.; Chang, M. N.;
Hwang, S.-B. Phytochemistry 1987, 26, 1377.
(7) Enders, D.; Kirchhoff, J.; Lausberg, V. Liebigs Ann. Chem.
1996, 1361.
CH2Cl2 (3 10 mL). The combined org. layers were dried with
MgSO4 and evaporated in vacuo. The crude product was purified
via column chromatography (Et2O pentane, 3:1) to give (+)-4 (42
mg, 85%) as an colorless oil.
(8) (a) Pirkle, W. H.; Hoover, D. J. Top. Stereochem. 1982, 13,
263. (b) Parker, D. Chem. Rev. 1991, 91, 1441.
(9) Ogiku, T.; Yoshida, S.-I.; Ohmizu, H.; Iwasaki, T. J. Org.
Chem. 1995, 60, 1148.
22
[ ]D22 +37.8 (c = 2.0, CHCl3); lit. 21a [ ]D 34.8 (c = 0.93, CHCl3).
IR (KBr): 3010 (m), 2935 (s), 1590 (vs), 1504 (vs), 1489 (vs), 1462
(s), 1445 (s), 1421 (s), 1243 (vs), 1128 (vs), 1039 (s), 755 (vs) cm .
1
(10) For previous syntheses of the racemate see: (a) ref.6.
(b) Pelter, A.; Ward, R. S.; Collins, P.; Venkateswarlu, R. J.
Chem. Soc., Perkin Trans. 1. 1985, 587. (c) Orito, K.;
Sasaki, T.; Suginome, H. J. Org. Chem. 1995, 60, 6208.
(11) Höke, M.; Hänsel, R. Arch. Pharm. (Weinheim, Ger.) 1972,
305, 33.
1H NMR (400 MHz, CDCl3): = 2.07 2.16 (m, 2 H, CH), 2.40
2.56 (m, 4 H, ArCH2), 3.44 (t, 1 H, J = 6.0 Hz, CH2O), 3.47 (t, 1 H,
J = 6.0 Hz, CH2O), 3.75 (s, 3 H, OCH3), 3.76 (s, 6 H, OCH3), 3.84
(t, 1 H, J = 6.6 Hz, CH2O), 3.86 (t, 1 H, J = 6.6 Hz, CH2O), 5.86 (dd,
2 H, J = 1.4, 4.1 Hz, OCH2O), 6.21 (s, 2 H, ArH), 6.46 6.49 (m, 2
H, ArH), 6.63 (d, 1 H, J = 8.0 Hz, ArH).
(12) For previous asymmetric syntheses see: (a) Takano, S.;
Ohkawa, T.; Tamori, S.; Satoh, S.; Ogasawara, K. J. Chem
Soc., Chem. Commun. 1988, 189. (b) Samizu, K.;
Ogasawara, K. Chem. Lett. 1995, 543.
(13) Hänsel, R.; Zander, D. Arch. Pharm. (Weinheim, Ger.) 1961,
294, 699.
13C NMR (100 MHz, CDCl3): = 39.52 (ArCH2), 40.26 (ArCH2),
46.72 (CH), 46.96 (CH), 56.36 (m-OCH3), 61.18 (p-OCH3), 73.55
(CH2O), 101.14 (OCH2O), 105.78, 108.28, 109.20, 121.69 (Ar),
134.28, 136.32, 136.57, 146.05, 147.84, 153.27, (Ar).
MS (EI, 70 eV): m/z (%) = 387 (20) [M+ + 1], 386 (85) [M+ ], 183
(11), 182 (100), 181 (25), 167 (13), 151 (17), 136 (7), 135 (20), 77
(6).
(14) Pal, S.; Mukhopadhyaya, J. K.; Ghatak, U. R. J. Org. Chem.
1994, 59, 2687.
(15) For previous asymmetric syntheses see: (a) Tomioka, K.;
Mizuguchi, H.; Koga, K. Chem. Pharm. Bull. 1982, 30,
4304. (b) Pelter, A.; Ward, R. S.; Jones, D. M.; Maddocks,
P. J. Chem. Soc., Perkin Trans. 1 1993, 2631. (c) Itoh, T.;
Chika, J.-I.; Takagi, Y.; Nishiyama, S. J. Org. Chem. 1993,
58, 5717. (d) Honda, T.; Kimura, N.; Sato, S.; Kato, D.;
Tominaga, H. J. Chem. Soc., Perkin Trans. 1 1994, 1043.
(16) (a) McDoniel, P. B.; Cole, J. R. J. Pharm. Sci. 1972, 61,
1992. (b) Chen, J.-J.; Ishikawa, T.; Duh, C.-Y.; Tsai, I.-L.;
Chen, I.-S. Planta Med. 1996, 62, 528.
HRMS: m/z calcd for C22H26O6 (M+): 386.1729; found, 386.17294.
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 380, Graduiertenkolleg 440) and the Fonds der Chemischen
Industrie. We thank the former Boehringer Mannheim GmbH for
providing us with L-acetonamine and Degussa AG, BASF AG, Bay-
er AG, and Aventis for the donation of chemicals.
(17) Planchenault, D.; Dhal, R.; Robin, J.-P. Tetrahedron 1993,
49, 5823.
References
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Synthesis 2002, No. 4, 515–522 ISSN 0039-7881 © Thieme Stuttgart · New York