Synthesis of (+)-aptosimon, a 4-oxofurofuran lignan, by erythro selective aldol condensation and stereoconvergent cyclization as the key reactions

Article abstract of DOI:10.1271/bbb.67.838

The 4-oxofurofuran lignan, (+)-aptosimon (1), was synthesized from γ-butyrolactone (9). To construct the two benzylic chiral center of (+)-aptosimon (1), highly erythro selective aldol condensation and stereoconvergent SN1 intramolecular cyclization were used as the key reactions.

Full text of DOI:10.1271/bbb.67.838

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Synthesis of (+)-Aptosimon, a 4-Oxofurofuran
Lignan, by erythro Selective Aldol Condensation and
Stereoconvergent Cyclization as the Key Reactions
Satoshi YAMAUCHIa & Munetoshi YAMAGUCHIa
a College of Agriculture, Ehime UniversityTarumi 3-5-7, Matsuyama, Ehime 790-8566,
Japan
Published online: 22 May 2014.
To cite this article: Satoshi YAMAUCHI & Munetoshi YAMAGUCHI (2003) Synthesis of (+)-Aptosimon, a 4-Oxofurofuran
Lignan, by erythro Selective Aldol Condensation and Stereoconvergent Cyclization as the Key Reactions, Bioscience,
Biotechnology, and Biochemistry, 67:4, 838-846, DOI: 10.1271/bbb.67.838
To link to this article: http://dx.doi.org/10.1271/bbb.67.838
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Biosci. Biotechnol. Biochem., 67 (4), 838–846, 2003
＋
Synthesis of ( )-Aptosimon, a 4-Oxofurofuran Lignan, by erythro Selective
Aldol Condensation and Stereoconvergent Cyclization as the Key Reactions
Satoshi YAMAUCHI† and Munetoshi YAMAGUCHI
College of Agriculture, Ehime University, Tarumi 3-5-7, Matsuyama, Ehime 790-8566, Japan
Received November 11, 2002; Accepted December 11, 2002
＋
The 4-oxofurofuran lignan, ( )-aptosimon (1),
was synthesized from -butyrolactone (9). To construct
g
＋
the two benzylic chiral center of ( )-aptosimon (1),
highly erythro selective aldol condensation and
stereoconvergent S 1 intramolecular cyclization were
N
used as the key reactions.
Fig.
Key words: lignan; furofuran lignan; aptosimon;
aldol condensation
＋
(
)-Aptosimon has been isolated from Aptosi-
benzylic position of 5 in the presence of a catalytic
amount of acid. Erythro aldol product 6 could be
converted to triol 5 by protection, reduction, and
selective removal of R1. The high erythro selectivity
mum spinescens1) and its structure corrected to that
of 1.2) Since 4-oxofurofuran lignan is a small group in
the furofuran series,3) only ˆve synthetic studies on
the racemate have been reported.4–8) Though many
types of biological activity for furofuran lignan have
been reported,9,10) e.g. antioxidative activity, an-
titumor activity, phosphodiesterase inhibition activi-
ty, and the eŠect on the central nervous system, the
structure-activity relationship is unknown. To con-
tribute to this biological research, and particularly to
study the relationship between activity and degree of
oxygenation of the furofuran structure, 1,2-oxyg-
enated furofuran lignan has been synthesized.11) As a
continuation of this research, the 4-oxofurofuran
in the aldol condensation between
and piperonal would be required to give 6. Aldol
product 8 could be converted to -butyrolactone 7.
This aldol product 8 would be obtained from
g-butyrolactone 7
g
g
-
butyrolactone 9 and piperonal; however, the erythro
or threo selectivity would not be necessary in this
step.
g-Butyrolactone 9 can be obtained from
L
-glutamic acid.13) The chiral center at the 2 position
of (
＋
)-aptosimon (1) could be converted from the 2?
position of 6, which could be obtained by erythro
selective aldol condensation, and the other chiral
center at the 6 position could be obtained by the
stereoconvergent cyclization of triol 5.
lignan, (
target compound in this work.
In this synthetic study, erythro or threo selectivity
in the aldol condensation of
methyl]-
um enolate is also interesting. In our previous study,
aldol condensation using the potassium enolate of
benzyl- -butyrolactone 3 and benzaldehydes showed
erythro selectivity.12) As a new substrate for this aldol
condensation, oxygenated -benzyl- -butyrolactone
2 is employed. The erythro selectivity in this aldol
condensation with 2 is very important in this project
(Fig.).
The retrosynthetic analysis of ( )-aptosimon (1) is
shown in Scheme 1. ( )-Aptosimon (1) could be
obtained by the cyclization of 4 followed by oxida-
tion. Tetrahydrofuran derivative 4 could be obtained
from triol 5 by employing stereoconvergent S
cyclization between oxygen at the 4 position and 1
＋
)-aptosimon (1), has been selected as the
b-[(aryl)(silyloxy)
g-butyrolactone 2 with piperonal via potassi-
Results and Discussion
The enantiomeric excess of the starting material
b
-
was determined before tritylation to 9 as 99z ee by
g
Mosher's method. The aldol condensation of g-
butyrolactone 913) with piperonal, using lithium
diisopropylamide, gave erythro aldol product 10
b
g
z z
(43 ) and threo aldol product 11 (43 ). Although
the erythro or threo selectivity at this stage was not
important, the next step was performed from sepa-
rated erythro aldol product 10 and threo aldol
product 11. The erythro and threo isomers were
determined by the coupling constant between 2-H
and the benzylic proton.14)
＋
＋
N
1
After the hydroxy group of erythro 10 had been
protected as a triisopropylsilyl ether (85 ), resulting
z
?
-
†
To whom correspondence should be addressed. Fax:
81-89-977-4364; E-mail: syamauch agr.ehime-u.ac.jp
＋ ＠

＋
Synthesis of ( )-Aptosimon
839
Scheme 1. Retrosynthetic Analysis of (
＋
)-Aptosimon (1).
and then by (n-Bu)4NF to give triol 23 in a quantita-
lactone 12 was subjected to LiAlH4 reduction and
tive yield in 3 steps. The treatment of 22 with LiAlH4
subsequent cleavage of the trityl ether in formic acid-
gave a desilylated product (scheme 3).
ether to give triol 13 in 69
z
yield in 2 steps. NaIO4
S 1 intramolecular etheriˆcation of triols 17 and
N
followed by Ag2CO3-celite oxidation of triol 13 gave
-butyrolactone 14 in 71 yield in 2 steps. This
23 was carried out by employing 10-camphorsulfonic
g
z
acid as a catalyst, giving stereoconvergently tetra-
lactone 14 was exposed to the important aldol
condensation requiring erythro selectivity. This
erythro selectivity was achieved by using potassium
bis(trimethylsilyl)amide as a base, giving erythro
hydrofuran derivative 24 as a single isomer in 61
z
and 57
z yield, respectively. The conversion of 17 to
24 proceeded smoothly, although that of 23 took a
long time. At this stage, the construction of two
aldol product 15 as a single isomer in 84
erythro conˆguration was conˆrmed by the coupling
constant between 2-H and benzylic 2
-H.14) After the
z yield. This
＋
benzylic chiral centers of ( )-aptosimon (1) was
accomplished. After pyridinium chlorochromate oxi-
?
dation of 24 to aldehyde 25 in 73
z
yield, subsequent
aque-
ous HCl solution and tetrahydrofuran gave hemia-
cetal 26 in 82 yield. Finally, hemiacetal 26 was
subjected to pyridinium chlorochromate oxidation to
hydroxy group had been protected as a methox-
ymethyl ether in a quantitative yield, lactone 16 was
transformed to triol 17 by LiAlH4 reduction and then
cleavage of the methoxymethyl ether in a 6
M
z
by cleavage of the silyl ether with (
yield in 2 steps (Scheme 2).
n-Bu)4NF in 75
z
＋
give ( )-aptosimon (1) in 84
of NOE between the two benzylic protons and 8
supports this absolute conˆguration (Scheme 4).
z
yield. The existence
Threo aldol product 11 was converted to lactone 20
in 54 overall yield by the same method as that
b
-H
z
described for the preparation of lactone 14. Aldol
condensation of the potassium enolate of lactone 20
with piperonal also gave erythro aldol product 21 as a
＋
(
)-Aptosimon (1) was thus synthesized from g-
butyrolactone 9, involving 14–15 steps in 6–10
z
overall yield. This is the ˆrst synthesis of optically
single isomer in 86
the presence of a silyloxy group at the benzylic posi-
tion of -benzyl- -butyrolactone did not reduce the
z yield. These results show that
active 4-oxofurofuran lignan, and highly erythro
selective aldol condensation of
b-[(aryl)(silyloxy)
b
g
methyl]-g-butyrolactone with piperonal, using
erythro selectivity and that the stereochemistry at this
benzylic position did not eŠect the erythro selectivity
in the aldol condensation via potassium enolate.
After protecting the hydroxy group as a methox-
KHMDS, was observed. The two benzylic chiral
＋
centers of ( )-aptosimon (1) were constructed by
this erythro selective aldol condensation and
stereoconvergent S 1 intramolecular cyclization.
N
ymethyl ether in 82
z yield, resulting lactone 22 was
treated with diisobutylaluminum hydride and NaBH4

840
S. YAMAUCHI and M. YAMAGUCHI
Scheme 2. Conversion to Triol 17.
－
(a) LDA, piperonal, THF, 75
(1) LiAlH4, THF, 0 C, 1 h; (2) HCO2H, ether, 10
toluene, re‰ux, 1 h (71 yield, 2 steps). (e) KHMDS, piperonal, THF, 75 yield). (f) MOMCl, DIPEA, CH2Cl2, r.t., 16 h
(100 yield). (g) (1) LiAlH4, THF, r.t., 30 min; (2) ( -Bu)4NF, THF, 0 C, 1 h (75z yield, 2 steps).
9
C, 1 h (10, 43
z
－
yield; 11, 43
z
yield). (b) TIPSOTf, 2,6-lutidine, CH2Cl2, 0
9C, 1 h (85z yield). (c)
9
9C, 10 min (69z yield, 2 steps). (d) (1) NaIO4, MeOH, r.t., 2 h; (2) Ag2CO3-celite,
－
z
9C, 1 h (84
z
z
n
9
Scheme 3. Conversion to Triol 23.
(a) TIPSOTf, 2,6-lutidine, CH2Cl2, 0
9
C, 1 h (90
z
yield). (b) (1) LiAlH4, THF, 0
9
C, 1 h; (2) HCO2H, ether,
yield, 2 steps). (d) KHMDS, piperonal,
yield). (f) (1) DIBAL-H, 75 C, 1 h; (2) NaBH4, EtOH,
－
10 C, 10 min (61
9 z
yield, 2 steps). (c) (1) NaIO4, MeOH, r.t., 2 h; (2) Ag2CO3-celite, toluene, re‰ux, 1 h (99
THF, 75 C, 1 h (86 yield). (e) MOMCl, DIPEA, CH2Cl2, r.t., 16 h (82
r.t., 2 h; (3) ( -Bu)4NF, THF, 0 C, 1 h (100 yield, 3 steps).
z
－
－
9
z
z
9
n
9
z
Wakogel C-300 (Wako, 200–300 mesh).
Experimental
All melting point (mp) data are uncorrected. NMR
data were measured by a JNM-EX400 spectrometer,
IR spectra were determined with a Shimadzu FTIR-
8100 spectrophotometer, FABMS data were meas-
ured with a JMS-MS700V spectrometer, and optical
rotation values were evaluated with a HORIBA
SEPA-200 instrument. The silica gel used was
(2S,4S)-2-[(S)-(Hydroxy)(3,4-methylenediox-
yphenyl)methyl]-5-trityloxy-4-pentanolide (10
) and
(2 S,4 S )-2-[( R )-(hydroxy)(3,4-methylenediox-
yphenyl)methyl]-5-trityloxy-4-pentanolide (11). To a
solution of LDA (0.067 mol) in THF (200 ml) was
added a solution of lactone 9 (20.0 g, 0.056 mol) in
THF (60 ml) at
－
75 C. After the solution was
9

＋
Synthesis of ( )-Aptosimon
841
Scheme 4. Conversion to (
(a) for 17: CSA, CH2Cl2, 3
yield). (c) aq. 6 HCl solution, THF, r.t., 5 h (82
＋
)-Aptosimon (1).
C, 4 h (61 yield); for 23: CSA, CH2Cl2, 3
yield). (d) PCC, MS 4A, CH2Cl2, r.t., 3 h (84
z
9
z
9
C, 40 h (57
z
yield). (b) PCC, MS 4A, CH2Cl2, r.t., 7 h (73
yield).
z
M
z
stirred at
－
75
9
C for 30 min, a solution of piperonal
134.4, 143.2, 147.6, 148.0, 179.4. IR nmax (CHCl3):
(12.6 g, 0.084 mol) in THF (40 ml) was added. The
reaction solution was stirred at 75
3503, 3017, 2878, 1754, 1505, 1489, 1449, 1250, 1183,
9C for 1 h, and
1098, 1042 cm－
.
Anal. Found: C, 75.55; H, 5.55
z.
1
－
then a sat. aq. NH4Cl solution was added. The
organic solution was separated, washed with brine,
and dried (Na2SO4). Concentration followed by silica
z
Calcd. for C32H28O6: C, 75.58; H, 5.55 .
(2 S,4 S )-2-[( S )-(3,4-Methylenedioxyphenyl)
(triisopropylsilyloxy)methyl]-5-trityloxy-4-pen-
tanolide (12). To an ice-cooled solution of erythro10
(13.0 g, 0.026 mol) and 2,6-lutidine (6.56 ml, 0.057
mol) in CH2Cl2 (100 ml) was added TIPSOTf
(7.69 ml, 0.029 mol). The reaction solution was
gel column chromatography (2
z
EtOAc benzene)
W
gave erythro 10 (12.2 g, 0.024 mol, 43
z
) as colorless
crystals, mp 135–136
9
C (iso-Pr2O benzene 1 1)
＝
W
W
and threo 11 (12.2 g, 0.024 mol, 43
z
) as colorless
＝
crystals, mp 158–159 C (iso-Pr2O benzene 1 1).
9
W
W
20＝＋
Erythro 10: [
a
]
1.1 (
c
0.94, CHCl3). NMR dH
9
stirred at 0 C for 1 h before addition of a sat. aq.
D
＝
(CDCl3): 1.80 (1H, ddd,
3- H), 2.40 (1H, ddd, 12.9, 9.3, 8.8 Hz, 3-
2.63 (1H, d,
3.9 Hz, 5-
2-H), 3.41 (1H, dd,
(1H, m, 4-H), 5.29 (1H, dd,
OH), 5.95 (2H, s, OCH2O), 6.77–6.80 (2H, m,
J
12.9, 9.8, 3.4 Hz,
NaHCO3 solution. The organic solution was separat-
ed, washed with a sat. aq. CuSO4 solution, sat. aq.
NaHCO3 solution, and brine, and dried (Na2SO4).
Concentration followed by silica gel column chro-
H
J
＝
H
H),
＝
10.7,
＝
J
3.9 Hz, OH), 3.08 (1H, dd,
H), 3.16 (1H, ddd, 9.8, 9.3, 2.9 Hz,
10.7, 3.2 Hz, 5-H ), 4.64
3.9, 2.9 Hz, Ar-
J
H
J
＝
＝
＝
J
H
matography (EtOAc hexane 1 19) gave silyl ether
W
W
＝
J
12 (14.6 g, 0.022 mol, 85
z
) as colorless crystals, mp
C
H
9
108–109 C. [a] c 1.66, CHCl3). NMR dH
2D0＝－6.0 (
ArH), 6.82–6.84 (1H, m, ArH), 7.20–7.30 (9H, m,
ArH), 7.35–7.38 (6H, m, ArH). NMR dC (CDCl3):
23.7, 48.1, 65.3, 71.1, 77.9, 87.0, 101.1, 106.0, 108.2,
118.6, 127.2, 127.9, 128.6, 135.7, 143.3, 147.0,
147.9, 178.1. IR nmax (CHCl3): 3500, 3011, 2961,
(CDCl3): 0.99–1.08 (21H, m, iso-Pr), 1.80 (1H, ddd,
12.7, 9.8, 3.4 Hz, 3- H), 2.65 (1H, ddd,
12.7, 8.8, 8.8 Hz, 3-H
8.8, 2.0 Hz, 2-H), 3.07 (1H, dd,
5- H), 3.39 (1H, dd, 10.5, 3.2 Hz, 5-
(1H, m, 4-H), 5.44 (1H, d,
J
＝
H
J
＝
＝
H
), 2.92 (1H, ddd,
J
9.8,
10.5, 4.2 Hz,
H), 4.65
＝
J 2.0 Hz, Ar-
＝
J
H
J
＝
H
1763, 1505, 1491, 1449, 1240, 1184, 1096, 1080,
1042 cm－
.
Anal. Found: C, 75.35; H, 5.59
z
.
CHOTIPS), 5.96 (2H, s, OCH2O), 6.75–6.79 (2H,
m, ArH), 6.81–6.83 (1H, m, ArH), 7.19–7.28 (9H,
m, ArH), 7.34–7.40 (6H, m, ArH). NMR dC
(CDCl3): 12.6, 17.9, 18.0, 23.0, 50.0, 65.5, 72.8,
77.7, 87.0, 101.0, 106.2, 108.1, 118.8, 127.1, 127.9,
128.6, 137.7, 143.4, 146.8, 147.6, 177.7. IR nmax
(CHCl3): 3063, 2946, 2869, 1771, 1505, 1489, 1443,
1
Calcd. for C32H28O6: C, 75.58; H, 5.55
z
. Threo 11:
20＝＋
[
a
]
35.4 (
c
0.74, CHCl3). NMR dH (CDCl3):
13.0, 9.3, 2.4 Hz, 3- H), 1.93
13.0, 10.3, 9.3 Hz, 3-H ), 3.09 (1H,
10.7, 3.9 Hz, C HOTr), 3.17 (1H, m, 2-H),
10.7, 3.4 Hz, CH OTr), 4.32 (1H,
D
1.80 (1H, ddd,
J
＝
H
＝
(1H, ddd,
J
H
＝
dd,
J
H
＝
3.43 (1H, dd,
J
H
＝
H
s, OH), 4.50 (1H, m, 4-H), 4.66 (1H, d,
J
8.8 Hz,
O), 5.96
O), 6.77–6.78 (2H, m,
1252, 1238, 1186, 1130, 1102, 1088, 1042, 1013,
980 cm－
.
Anal. Found: C, 74.17; H, 7.58
z
. Calcd.
1
ArC
H
OH), 5.96 (1H, d,
J
＝
6.6 Hz, OCH
＝
(1H, d, J 6.6 Hz, OCH
H
for C41H48O6Si: C, 74.06; H, 7.28z.
ArH), 6.88 (1H, s, ArH), 7.22–7.32 (9H, m, ArH),
7.36–7.38 (6H, m, ArH). NMR dC (CDCl3): 27.5,
46.3, 65.0, 74.9, 77.5, 87.3, 101.1, 106.8, 108.1,
120.4, 127.2, 127.3, 127.9, 128.0, 128.6, 128.7,
(2 S,4 R )-4-[( S )-(3,4-Methylenedioxyphenyl)
(triisopropylsilyloxy)methyl]pentane-1,2,5-triol (13).
To an ice-cooled suspension of LiAlH4 (0.98 g,

842
S. YAMAUCHI and M. YAMAGUCHI
0.026 mol) in THF (20 ml) was added a solution of
176.8. IR
1449, 1252, 1240, 1184, 1096, 1080, 1042 cm－
Found: C, 64.19; H, 8.39 . Calcd. for C21H32O5Si:
C, 64.25; H, 8.22
nmax (CHCl3): 3013, 2880, 1763, 1505, 1491,
1
lactone 12 (17.3 g, 0.026 mol) in THF (80 ml). The
. Anal.
reaction mixture was stirred at 0
9
C for 1 h before ad-
z
ditions of a sat. aq. MgSO4 solution and K2CO3. The
mixture was stirred at room temperature for 30 min
and then ˆltered. The ˆltrate was concentrated to
give a crude diol. To a solution of this crude diol in
ether (1000 ml) was added formic acid (1000 ml) at
z.
(2S,3R)-2-[(S )-(Hydroxy)(3,4-methylenediox-
yphenyl)methyl]-3-[( S )-(3,4-methylenediox-
yphenyl)(triisopropylsilyloxy)methyl]-4-butanolide
－
－
M
10
9
C. After the reaction solution was stirred at
(15). To a solution of KHMDS (20.0 ml, 0.5 in
9
10 C for 10 min, EtOAc and H O were added. The
toluene, 10.0 mmol) in THF (80 ml) was added a
solution of lactone 14 (2.50 g, 6.37 mmol) in THF
2
organic solution was separated, washed with a sat.
aq. NaHCO3 solution and brine, and dried (Na2SO4).
Concentration followed by silica gel column chro-
－
－
75
(20 ml) at
75
9C. After stirring at
9C for
15 min, piperonal (1.50 g, 9.99 mmol) in THF
(10 ml) was added. The reaction solution was stirred
＝
matography (EtOAc hexane 1 1) gave triol 13
W
W
20
D
(7.68 g, 0.018 mol, 69
z
) as a colorless oil. [
a
]
＝
9
at 75 C for 1 h, and then a sat. aq. NH4Cl solution
－
－
32.3 (
c
1.74, CHCl3). NMR
d
H (CDCl3): 0.97–1.07
was added. The organic solution was separated,
washed with brine, and dried (Na2SO4). Concentra-
tion followed by silica gel column chromatography
＝
(21H, m, iso-Pr), 1.18 (1H, ddd,
J
14.2, 8.8, 2.9
14.2, 9.8, 4.4 Hz,
H), 2.15 (1H, br. s, OH), 2.29 (1H, m, 4-H),
2.90–3.15 (2H, br., OH), 3.41 (1H, dd, 10.7, 7.3
10.7, 5.4 Hz), 3.56 (1H, br. d,
＝
H), 1.52 (1H, ddd, J
Hz, 3-H
3-
＝
H
(EtOAc hexane 1 9) gave erythro aldol product 15
W
W
20
D
J
＝
(2.90 g, 5.34 mmol, 84
z
) as a colorless oil. [
a
]
＝
＝
＋
20.9 (
Hz), 3.48 (1H, dd,
J
c
2.15, CHCl3). NMR dH (CDCl3): 0.85–1.00
＝
＝
＝
(21H, m, iso-Pr), 2.61 (1H, d, J 3.9 Hz, OH), 2.75
J
10.7 Hz), 3.72 (1H, dd,
(1H, m, 2-H), 4.87 (1H, d,
CHOTIPS), 5.96 (2H, s, OCH2O), 6.73–6.78 (2H,
J
10.7, 6.4 Hz), 3.80
＝
＝
4.9, 2.9 Hz, 2-H), 2.85 (1H, m, 3-H),
J
4.9 Hz, Ar-
(1H, dd,
4.32 (1H, dd,
9.0, 8.3 Hz, 4-H
CHOTIPS), 5.22 (1H, dd,
J
＝
J
9.0, 4.6 Hz, 4-
H
H), 4.38 (1H, dd,
4.4 Hz, Ar-
＝
J 3.9, 2.9 Hz, Ar-
J
m, ArH), 6.86 (1H, s, ArH). NMR
d
C (CDCl3): 12.3,
＝
H
), 4.63 (1H, d, J
＝
17.9, 18.0, 31.8, 44.4, 63.4, 67.0, 70.1, 78.0, 101.0,
＝
107.5, 107.7, 120.4, 135.7, 146.8, 147.4. IR nmax
C
H
OH), 5.93 (2H, s, OCH2O), 5.96 (1H, d,
J
7.1
(CHCl3): 3629, 2946, 2869, 1505, 1489, 1443, 1242,
Hz, OC
H
HO), 5.97 (1H, d,
J
＝
7.1 Hz, OCH
H
O),
1084, 1042 cm－
.
Anal. Found: C, 61.70; H, 8.96
z.
6.42 (1H, dd,
J
7.8, 1.5 Hz, ArH), 6.45 (1H, d,
J
1
＝
＝
Calcd. for C22H38O6Si: C, 61.94; H, 8.98
z
.
1.5 Hz, ArH), 6.61 (1H, d,
J
＝
7.8 Hz, ArH),
6.67–6.70 (3H, m, ArH). NMR dC (CDCl3): 12.5,
×
(3 R )-3-[( S )-(3,4-Methylenedioxyphenyl)
(triisopropylsilyloxy)methyl]-4-butanolide 14).
17.9, 18.0, 43.0, 48.9, 70.0, 72.7, 75.6, 101.1 (C 2),
(
A
106.0, 106.5, 107.7, 108.0, 118.6, 119.5, 134.8,
reaction mixture of triol 13 (3.51 g, 8.23 mmol) and
NaIO4 (1.93 g, 9.04 mmol) in MeOH (30 ml) was
stirred at room temperature for 2 h. After its concen-
tration, the resulting residue was dissolved in H2O
and EtOAc. The organic solution was separated,
washed with brine, and dried (Na2SO4). Concentra-
tion gave a crude hemiacetal. A reaction mixture of
this crude hemiacetal and Ag2CO3-celite (9.04 g, con-
taining ca. 9.04 mmol of Ag2CO3) in toluene (80 ml)
was heated under re‰ux for 1 h. After the mixture
was ˆltered, the ˆltrate was concentrated. The
residue was applied to silica gel column chro-
135.1, 146.9, 147.5, 147.7, 178.4. IR nmax (CHCl3):
3611, 2926, 1761, 1505, 1491, 1445, 1254, 1242, 1196,
1084, 1067, 1042 cm－
. Anal. Found: C, 63.92; H,
1
6.86
z. Calcd. for C29H38O8Si: C, 64.18; H, 7.06z.
(2 S, 3R )-2-[( S )-( Me tho xym eth oxy)(3, 4-
methylenedioxyphenyl)methyl]-3-[( S )-(3,4-
methylenedioxyphenyl)(triisopropylsilyloxy)methyl]-
4-butanolide (16). A reaction mixture of alcohol 15
(2.56 g, 4.72 mmol), DIPEA (12.8 ml, 73.5 mmol),
and MOMCl (2.80 ml, 36.9 mmol) in CH2Cl2 (5 ml)
was stirred at room temperature for 16 h before the
additons of MeOH, H2O, and CH2Cl2. The organic
＝
matography (EtOAc hexane 1 4) to give lactone 14
W
W
20
D
＝
M
(2.28 g, 5.81 mmol, 71
z
) as a colorless oil. [
a
]
solution was separated, washed with 1 aq. HCl
solution, sat. aq. NaHCO3 solution, and brine, and
dried (Na2SO4). Concentration followed by silica gel
－
49.5 (c 1.56, CHCl3). NMR dH (CDCl3): 0.96–1.04
＝
(21H, m, iso-Pr), 2.54 (1H, dd,
J
17.6, 8.8 Hz,
17.6, 7.8 Hz, 2-H ), 2.85
9.3, 6.8 Hz, 4- H),
), 4.69 (1H, d,
3.9 Hz,
O), 6.71
＝
＝
2-
H
H), 2.62 (1H, dd,
J
H
column chromatography (EtOAc hexane 1 9) gave
W
W
＝
(1H, m, 3-H), 4.09 (1H, dd,
J
H
MOM ether 16 (2.77 g, 4.72 mmol, 100
z
) as color-
D
＝
20＝－
4.15 (1H, dd,
＝
OC
(1H, dd,
J
9.3, 7.8 Hz, 4-H
H
J
less crystals, mp 108–109
9C (MeOH). [
a
]
40.0
6.3 Hz, ArCHOTIPS), 5.97 (1H, d,
J
＝
H
(c 3.57, CHCl3). NMR dH (CDCl3): 0.90–1.00 (21H,
＝
＝
H
HO), 5.97 (1H, d,
J
3.9 Hz, OCH
m, iso-Pr), 2.72 (1H, dd,
(1H, m, 3-
9.0, 3.6 Hz, 4-
4-H
3.9 Hz, ArC
J
3.9, 2.9 Hz, 2-
H
), 2.90
＝
＝
＝
3), 4.36 (1H, dd, J
J
7.8, 1.5 Hz, ArH), 6.76 (1H, d,
J
7.8
H
), 3.32 (3H, s, OC
H
＝
＝
9.0, 6.1 Hz,
Hz, ArH), 6.81 (1H, d,
J
1.5 Hz, ArH). NMR dC
H
H), 4.46 (1H, dd,
J
＝
J
(CDCl3): 12.4, 17.9, 18.0, 31.0, 44.5, 69.5, 75.5,
101.1, 106.7, 108.0, 119.8, 135.9, 147.4, 147.9,
H
), 4.52 (2H, s, OC
H
2OCH3), 4.65 (1H, d,
H
OTIPS), 5.17 (1H, d, J 2.4 Hz, Ar-
＝

＋
Synthesis of ( )-Aptosimon
843
CHOMOM), 5.92–5.98 (4H, m, OC
H
2O), 6.35–6.37
), 6.62 (1H, d,
18 (12.1 g, 0.018 mol, 90
z
) as colorless crystals, mp
20＝＋
(2H, m, ArH), 6.57–6.59 (2H, m, Ar
H
118–119
9C (iso-Pr2O). [
a
]
20.4 (
c
1.18, CHCl3).
3)2),
D
＝
＝
7.8 Hz, Ar
J
7.8 Hz, Ar
H
), 6.69 (1H, d,
J
H
).
NMR dH (CDCl3): 0.98–1.02 (18H, m, CH(C
1.05–1.16 (3H, m, C (C 3)2), 2.06 (1H, ddd,
13.4, 10.3, 5.4 Hz, 3- H), 2.23 (1H, ddd, 13.4,
8.3, 6.7 Hz, 3-H ), 2.94 (1H, dd, 10.7, 3.9 Hz,
5- H), 3.34 (1H, dd, 10.7, 2.9 Hz, 5-H ), 3.41
(1H, ddd, 10.3, 6.7, 3.9 Hz, 2-H), 3.94 (1H, m,
4-H), 5.40 (1H, d,
(2H, s, OCH2O), 6.74 (1H, d,
H
＝
J
NMR dC (CDCl3): 12.5, 17.9, 43.0, 48.4, 56.0, 70.1,
H
H
75.8 (C
×
2), 94.3, 101.1, 101.2, 106.4, 106.5, 107.6,
H
J
＝
＝
J
108.1, 119.4, 132.3, 134.9, 146.8, 147.1, 147.4,
H
＝
147.8, 177.7. IR nmax (CHCl3): 2548, 2869, 1765,
H
J
H
1505, 1489, 1445, 1252, 1242, 1100, 1042, 1026 cm－
.
1
＝
J
＝
Anal. Found: C, 63.39; H, 7.13
C31H42O9Si: C, 63.46; H, 7.22
z
. Calcd. for
J
3.9 Hz, ArCHOTIPS), 5.94
7.8 Hz, ArH), 6.85
7.8, 1.5 Hz, ArH), 6.91 (1H, d,
z
.
J
＝
＝
＝
1.5
(1H, dd,
J
J
(2R,3R)-2-[(S )-( Hydroxy)(3,4-methylenediox-
yphenyl)methyl]-3-[(S )-(methoxymethoxy)(3,4-
methylenedioxyphenyl)methyl]butane-1,4-diol (17).
To an ice-cooled suspension of LiAlH4 (0.18 g,
4.74 mmol) in THF (10 ml) was added a solution of
lactone 16 (2.80 g, 4.77 mmol) in THF (20 ml). The
Hz, ArH), 7.20–7.30 (9H, m, ArH), 7.38–7.43 (6H,
m, ArH). NMR dC (CDCl3): 12.2, 17.9, 18.0, 24.3,
49.5, 65.1, 72.9, 77.8, 86.9, 101.0, 107.3, 107.9,
120.0, 127.1, 127.9, 128.6, 134.2, 143.5, 147.1,
147.5, 176.8. IR nmax (CHCl3): 3036, 2946, 2869,
1763, 1505, 1489, 1449, 1254, 1240, 1199, 1100, 1092,
1
resulting reaction mixture was stirred at 0
9
C for
1042, 1017 cm－
.
Anal. Found: C, 74.03; H, 7.35
z
.
30 min before additions of a sat. aq. MgSO4 solution
and K2CO3. After stirring at room temperature for 30
min, the mixture was ˆltered, and the resulting
ˆltrate was concentrated to give a crude diol. To an
ice-cooled solution of this crude diol in THF (30 ml)
Calcd. for C41H48O6Si: C, 74.06; H, 7.28z.
(2 S,4 R )-4-[( R )-(3,4-Methylenedioxyphenyl)
(triisopropylsilyloxy)methyl]pentane-1,2,5-triol (19).
To an ice-cooled suspension of LiAlH4 (0.68 g,
0.018 mol) in THF (10 ml) was added a solution of
lactone 18 (12.1 g, 0.018 mol) in THF (60 ml). The
was added
5.25 mmol). After the reaction solution was stirred at
C for 1 h, a sat. aq. NH4Cl solution was added.
(
n
-Bu)4NF (5.25 ml,
1
M
in THF,
0
9
9
reaction mixture was stirred at 0 C for 1 h before ad-
The organic solution was separated, washed with
brine, and dried (Na2SO4). Concentration followed
ditions of a sat. aq. MgSO4 solution and K2CO3. The
mixture was stirred at room temperature for 30 min
and ˆltered. The resulting ˆltrate was concentrated
to give a crude diol. To a solution of this crude diol
in ether (900 ml) was added formic acid (900 ml) at
－
by silica gel column chromatography (EtOAc hexane
W
＝
z
1 1) gave triol 17 (1.56 g, 3.59 mmol, 75 ) as
W
＝
1
colorless crystals, mp 93–94
4). [
W
9
C (MeOH iso-Pr2O
W
20＝－
a
]
129 (
c
1.22, CHCl3). NMR
d
H (CDCl3):
10
10
9C. After the reaction solution was stirred at
D
2.21 (1H, m), 2.34 (1H, m), 3.33 (3H, s, OCH3), 3.60
－
9
C for 10 min, EtOAc and H2O were added. The
＝
＝
H
(1H, dd,
(1H, dd,
J
10.2, 8.3 Hz), 3.72–3.79 (2H, m), 3.89
organic solution was separated, washed with a sat.
aq. NaHCO3 solution and brine, and dried (Na2SO4).
Concentration followed by silica gel column chro-
J
10.2, 4.6 Hz), 3.91–4.09 (3H, br.), 4.46
＝
(2H, s, OC
2OCH3), 4.72 (1H, d,
J
6.4 Hz, Ar-
5.4 Hz, ArCHOMOM),
＝
＝
C
H
OH), 4.91 (1H, d,
J
matography (EtOAc hexane 1 1) gave triol 19
W
W
20
D
5.92–5.95 (4H, m, OCH2O), 6.56–6.60 (4H, m,
ArH), 6.63–6.67 (2H, m, ArH). NMR dC (CDCl3):
44.2, 45.0, 56.3, 61.3, 61.6, 73.8, 78.2, 94.4, 100.9,
101.0, 106.3, 107.0, 107.7, 107.8, 119.0, 120.6,
133.4, 137.1, 146.4, 147.0, 147.4, 147.7. IR nmax
(4.69 g, 0.011 mol, 61
z
) as a colorless oil. [
a
]
＝
＋
21.8 (
c
1.10, CHCl3). NMR dH (CDCl3): 0.96–1.03
(21H, m, iso-Pr), 1.33 (1H, ddd,
J
＝
14.5, 8.1, 2.9
＝
HH), 1.50 (1H, ddd, J
Hz, 3-
3-H
2.77 (1H, br. s, OH), 3.42 (1H, br. dd,
14.5, 9.4, 4.9 Hz,
H
), 2.11 (1H, m, 4-H), 2.38 (1H, br. s, OH),
(CHCl3): 3420, 2869, 1505, 1489, 1445, 1242,
J
＝
8.8, 8.3
1042 cm－
.
Anal. Found: C, 60.82; H, 6.03
z.
Hz), 3.50–3.58 (2H, m), 3.62 (1H, dd,
J
11.2, 5.9
1
＝
Calcd. for C22H26O9: C, 60.93; H, 6.08
z
.
Hz), 3.67 (1H, dd,
2-H), 4.90 (1H, d,
J
＝
＝
10.7, 4.9 Hz), 3.79 (1H, m,
5.4 Hz, ArCHOTIPS), 5.95
J
(2 S,4 S )-2-[( R )-(3,4-Methylenedioxyphenyl)
(triisopropylsilyloxy)methyl]-5-trityloxy-4-pen-
tanolide (18). To an ice-cooled solution of threo-11
(10.3 g, 0.020 mol) and 2,6-lutidine (5.16 ml,
0.045 mol) in CH2Cl2 (100 ml) was added TIPSOTf
(5.96 ml, 0.022 mol). The reaction solution was
(2H, s, OCH2O), 6.73–6.77 (2H, m, ArH), 6.86 (1H,
s, ArH). NMR dC (CDCl3): 12.4, 17.9, 18.0, 31.2,
45.5, 63.2, 67.0, 70.3, 77.2, 100.9, 107.5, 107.7,
120.3, 136.3, 146.8, 147.5. IR nmax (CHCl3): 3400,
2946, 2869, 1505, 1489, 1442, 1244, 1090, 1042,
884 cm－
.
Anal. Found: C, 62.04; H, 9.02
z. Calcd.
1
stirred at 0
9
C for 1 h before addition of sat. aq.
z
for C22H38O6Si: C, 61.94; H, 8.98 .
NaHCO3 solution. The organic solution was separat-
ed, washed with a sat. aq. CuSO4 solution, sat. aq.
NaHCO3 solution, and brine, and dried (Na2SO4).
Concentration followed by silica gel column chro-
(3 R )-3-[( R )-(3,4-Methylenedioxyphenyl)
(triisopropylsilyloxy)methyl]-4-butanolide
(20). A
reaction mixture of triol 19 (2.30 g, 5.39 mmol) and
NaIO4 (1.27 g, 5.94 mmol) in MeOH (30 ml) was
matography (EtOAc hexane
＝
1 19) gave silyl ether
W
W

844
S. YAMAUCHI and M. YAMAGUCHI
stirred at room temperature for 2 h. After its concen-
tration, the resulting residue was dissolved in H2O
and EtOAc. The organic solution was separated,
washed with brine, and dried (Na2SO4). Concentra-
tion gave a crude hemiacetal. A reaction mixture of
this crude hemiacetal and Ag2CO3-celite (5.86 g, con-
taining ca. 5.86 mmol of Ag2CO3) in toluene (80 ml)
was heated under re‰ux for 1 h. After the mixture
was ˆltered, the ˆltrate was concentrated. The
residue was applied to silica gel column chro-
(2 S , 3 R )-2-[( S )-(M eth oxym eth oxy)( 3, 4-
methylenedioxyphenyl)methyl]-3-[( R )-(3,4-
methylenedioxyphenyl)(triisopropylsilyloxy)methyl]-
4-butanolide (22). A reaction mixture of alcohol 21
(2.50 g, 4.61 mmol), DIPEA (12.9 ml, 74.1 mmol),
and MOMCl (2.80 ml, 36.9 mmol) in CH2Cl2 (5 ml)
was stirred at room temperature for 16 h before addi-
tions of MeOH, H2O, and CH2Cl2. The organic solu-
tion was separated, washed with a 1
M
aq. HCl solu-
tion, sat. aq. NaHCO3 solution, and brine, and dried
(Na2SO4). Concentration followed by silica gel
＝
matography (EtOAc hexane 1 4) to give lactone 20
W
W
20
D
＝
＝
(2.10 g, 5.35 mmol, 99
z
) as a colorless oil. [
a
]
column chromatography (EtOAc hexane 1 9) gave
W
W
＋
49.3 (
c
1.02, CHCl3). NMR
d
H (CDCl3): 0.95–1.00
MOM ether 22 (2.21 g, 3.77 mmol, 82
z
) as a color-
0.80, CHCl3). NMR dH
＝
20＝－
(21H, m, iso-Pr), 2.29 (1H, dd,
J
17.6, 8.3 Hz,
H), 2.82
9.3, 7.3 Hz, 4- H),
9.3, 6.8 Hz, 4-H ), 4.64 (1H, d,
less oil. [
a
]
43.8 (
c
D
2-H
H), 2.34 (1H, dd,
J
＝
17.6, 8.3 Hz, 2-
H
(CDCl3): 0.87–0.96 (21H, m, iso-Pr), 2.47 (1H, dd,
J
＝
＝
(1H, m, 3-H), 4.34 (1H, dd,
J
H
3.4, 2.9 Hz, 2-H), 2.79 (1H, m, 3-H), 3.32 (3H, s,
＝
＝
4.37 (1H, dd,
＝
J
H
J
OCH3), 4.24 (1H, d,
J
7.8 Hz, ArCHOTIPS), 4.37
H), 4.52 (2H, s,
＝
8.8, 7.8 Hz, 4-
6.8 Hz, ArCHOTIPS), 5.97 (2H, s, OCH2O), 6.72
(1H, dd,
OC
5.14 (1H, d,
J
H
＝
＝
＝
2OCH3), 4.64 (1H, dd, J 8.9, 3.2 Hz, 4-H
(1H, d,
J
7.8 Hz, ArH), 6.76 (1H, d,
J
7.8 Hz,
H
H),
ArH), 6.79 (1H, s, ArH). NMR dC (CDCl3): 12.5,
17.9, 18.0, 31.1, 44.7, 70.3, 75.8, 101.1, 106.6, 108.0,
119.9, 136.2, 147.4, 147.9, 176.6. IR nmax (CHCl3):
J
＝
2.4 Hz, ArCHOMOM), 5.90–5.99
(4H, m, OCH2O), 6.37 (1H, s, ArH), 6.40 (1H, d,
J
＝
8.3 Hz, ArH), 6.51–6.56 (2H, m, ArH), 6.60 (1H,
＝
7.8 Hz, ArH). NMR dC
2948, 2869, 1775, 1505, 1489, 1445, 1244, 1179, 1103,
s, ArH), 6.66 (1H, d,
J
1084, 1042, 1015, 884 cm－
.
Anal. Found: C, 64.50;
(CDCl3): 12.4, 17.8, 17.9, 43.9, 50.4, 56.1, 69.4,
75.4, 75.9, 94.3, 101.1, 101.2, 106.3, 106.4, 107.2,
108.1, 119.2, 120.3, 131.9, 135.6, 147.0, 147.1,
147.5, 147.8, 177.8. IR nmax (CHCl3): 2948, 1767,
1
H, 8.33
8.22
z
. Calcd. for C21H32O5Si: C, 64.25; H,
z
.
(2S,3R)-2-[(S )-( Hydroxy)(3,4-methylenediox-
yphenyl)methyl]-3-[( R )-(3,4-methylenediox-
yphenyl)(triisopropylsilyloxy)methyl]-4-butanolide
1732, 1505, 1489, 1445, 1248, 1100, 1042, 1026,
909 cm－
.
Anal. Found: C, 63.48; H, 6.92
z. Calcd.
1
for C31H42O9Si: C, 63.46; H, 7.22
z
.
(
21). To a solution of KHMDS (16.0 ml, 0.5
M
in
toluene, 8.00 mmol) in THF (80 ml) was added a
(2R,3R)-2-[(R)-(Hydroxy)(3,4-methylenediox-
yphenyl)methyl]-3-[(S )-(methoxymethoxy)(3,4-
solution of lactone 20 (2.10 g, 5.35 mmol) in THF
(20 ml) at
－
－
75
75
9C. After stirring at
9C for
methylenedioxyphenyl)methyl]butane-1,4-diol
To a solution of lactone 22 (2.11 g, 3.60 mmol) in
toluene (20 ml) was added DIBAL-H (3.84 ml, 1 in
C. After stirring at
aq. HCl solution was added.
(23).
15 min, piperonal (1.21 g, 8.03 mmol) in THF
(10 ml) was added. The reaction solution was stirred
M
－
at 75
－
75
9C for 1 h, and then a sat. aq. NH4Cl solution
toluene, 3.84 mmol) at
75 C for 1 h, a 1
9
was added. The organic solution was separated,
washed with brine, and dried (Na2SO4). Concentra-
tion followed by silica gel column chromatography
－
9
M
The organic solution was separated, washed with a
sat. aq. NaHCO3 solution and brine, and dried
(Na2SO4). Concentration gave a crude hemiacetal.
To an ice-cooled solution of this crude hemiacetal in
EtOH (20 ml) was added NaBH4 (0.15 g, 3.97 mmol).
The reaction mixture was stirred at room tempera-
＝
(EtOAc hexane 1 9) gave erythro aldol product 21
W
W
20
D
＝
(2.50 g, 4.61 mmol, 86
23.6 ( 1.27, CHCl3). NMR
(21H, m, iso-Pr), 2.54 (1H, dd,
z) as a colorless oil. [
a
]
＋
c
dH (CDCl3): 0.87–0.93
＝
J
3.4, 3.4 Hz, 2-H),
2.64 (1H, d,
J
＝
＝
4.4 Hz, OH), 2.72 (1H, m, 3-H),
7.3 Hz, ArCHOTIPS), 4.32 (1H, dd,
ture for 2 h before addition of a 1
M
aq. HCl solu-
4.26 (1H, d,
J
tion. After neutralization with a sat. aq. NaHCO3
solution, the mixture was concentrated. The resulting
residue was dissolved in EtOAc and H2O. The organ-
ic solution was separated, washed with brine, and
dried (Na2SO4). Concentration gave a crude diol. To
an ice-cooled solution of this crude diol in THF
＝
＝
8.8, 3.9
J
8.8, 8.3 Hz, 4-
H
H), 4.59 (1H, dd,
J
Hz, 4-H
ArC
(2H, m, ArH), 6.56–6.60 (2H, m, ArH), 6.63 (1H, s,
H
), 5.16 (1H, dd,
J
＝
4.4, 3.4 Hz,
H
OH), 5.91–5.98 (4H, m, OCH2O), 6.40–6.44
＝
7.8 Hz, ArH). NMR dC
ArH), 6.67 (1H, d,
J
(CDCl3): 12.4, 17.8, 18.0, 43.8, 50.6, 69.6, 72.6,
75.5, 101.1, 101.2, 105.8, 106.5, 107.4, 107.9, 118.4,
119.9, 134.8, 135.7, 146.9, 147.0, 147.5, 147.7,
(20 ml) was added (
n
-Bu)4NF (3.80 ml, 1
M
THF,
3.80 mmol). The reaction solution was stirred at 0
9
C
for 1 h before addition of a sat. aq. NH4Cl solution.
The organic solution was separated, washed with
brine, and dried (Na2SO4). Concentration followed
178.5. IR
1489, 1445, 1244, 1096, 1042 cm－
64.39; H, 7.23 . Calcd. for C29H38O8Si: C, 64.18;
H, 7.06
nmax (CHCl3): 3500, 2948, 2869, 1759, 1505,
1
.
Anal. Found: C,
z
by silica gel column chromatography (EtOAc hexane
W
＝
1 1) gave triol 23 (1.56 g, 3.59 mmol, 100 ) as a
z
z
.
W

＋
Synthesis of ( )-Aptosimon
845
20＝－
colorless oil. [
a
]
116 (
c
0.76, CHCl3). NMR dH
ˆltrate was concentrated. The residue was applied to
D
＝
(CDCl3): 1.75–1.88 (3H, m), 2.39 (1H, m), 3.32 (3H,
silica gel column chromatography (EtOAc hexane
W
＝
＝
s, OCH3), 3.45 (1H, ddd,
br. s, OH), 3.74 (1H, dd,
J
J
11.5, 4.6 Hz), 3.50 (1H,
11.5, 3.7 Hz), 3.93 (1H,
1 9) to give aldehyde 25 (0.44 g, 1.06 mmol, 73
z
) as
W
20＝－
a colorless oil. [
a
]
77.7 (c 4.00, CHCl3). NMR
D
dd,
4.45 (2H, s, OC
ArCHOR), 4.77 (1H, d,
J
＝
11.7, 2.5 Hz), 4.04 (1H, dd,
J
＝
11.7, 4.4 Hz),
dH (CDCl3): 3.13 (1H, m, 4-H), 3.24 (1H, ddd, J
＝
＝
H
2OCH3), 4.73 (1H, d,
J
7.8 Hz,
8.6, 6.8, 2.4 Hz, 3-H), 3.29 (3H, s, OCH3), 3.58 (1H,
＝
＝
＝
J
7.3 Hz, ArCHOR), 5.94
dd,
Hz, 5-H
4.42 (1H, d,
10.3 Hz, ArCHOMOM), 5.32 (1H, d,
2-H), 5.93 (2H, s, OCH2O), 5.97 (1H, d,
J
9.3, 7.3 Hz, 5-
H
H), 3.79 (1H, dd,
J
H
9.3, 6.8
HOCH3),
＝
(2H, s, OCH2O), 5.95 (2H, s, OCH2O), 6.66–6.67
(3H, m, ArH), 6.69–6.73 (3H, m, ArH). NMR dC
(CDCl3): 44.1, 47.6, 56.1, 59.5, 60.4, 76.3, 77.4,
H
), 4.37 (1H, d,
J
6.8 Hz, OC
＝
J
6.8 Hz, OCH
H
OCH3), 4.53 (1H, d,
J
＝
J
J
＝
＝
6.8 Hz,
2.9 Hz,
×
94.4, 101.0 (C 2), 106.7, 107.2, 107.9, 120.0, 120.9,
＝
133.7, 137.0, 146.9, 147.1, 147.8. IR nmax (CHCl3):
OC
H
HO), 5.97 (1H, d,
J
2.9 Hz, OCH
H
O),
3375, 2894, 1505, 1489, 1443, 1246, 1042 cm－
.
6.74–6.77 (4H, m, ArH), 6.80–6.81 (2H, m, ArH),
1
HRMS (FAB) m z (M＋ H): calcd. for C22H25O9,
10.06 (1H, d,
J
2.4 Hz, CHO). NMR dC (CDCl3):
－
＝
W
433.1498; found, 433.1499.
50.3, 56.8, 61.7, 70.4, 76.4, 80.1, 94.2, 101.0, 101.2,
106.2, 107.0, 108.2, 108.3, 119.0, 121.4, 133.0,
(2S,3R,4R)-3-Hydroxymethyl-4-[(S )-(methox-
ymethoxy)(3,4-methylenedioxyphenyl)methyl]-2-
(3,4-methylenedioxyphenyl)tetrahydrofuran (24). 1)
A reaction solution of triol 17 (1.20 g, 2.76 mmol)
and CSA (10 mg, 0.043 mmol) in CH2Cl2 (5 ml) was
135.4, 147.1, 147.8, 148.3, 200.0. IR nmax (CHCl3):
2894, 1717, 1505, 1489, 1447, 1244, 1098, 1042 cm－
.
1
Anal. Found: C, 63.72; H, 5.59
C22H22O8: C, 63.76; H, 5.53
z. Calcd. for
z
.
stood at 3
9
C for 4 h before addition of a few drops of
(1R,2S,4R S,5S,6S )-4-Hydroxy-2,6-bis(3,4-
W
Et3N. Concentration followed by silica gel column
methylenedioxyphenyl)-3,7-dioxabicyclo[3.3.0]
＝
chromatography (EtOAc hexane 1 2) gave tetra-
octane (26). A reaction solution of MOM ether 25
W
W
hydrofuran derivative 24 (0.70 g, 1.68 mmol, 61
z
)
(0.30 g, 0.72 mmol) in THF (10 ml) and a 6
M
aq.
as colorless crystals, mp 73–74
9
C (iso-Pr2O). 2) A
HCl solution (15 ml) was stirred at room temperature
for 5 h before addition of EtOAc. The organic solu-
tion was separated, washed with sat. aq. NaHCO3
solution, and brine, and dried (Na2SO4). Concentra-
tion followed by silica gel column chromatography
reaction solution of triol 23 (0.10 g, 0.23 mmol) and
CSA (3 mg, 0.013 mmol) in CH2Cl2 (5 ml) was stood
at 39C for 40 h before addition of a few drops of
Et3N. Concentration followed by silica gel column
＝
＝
chromatography (EtOAc hexane 1 2) gave tetra-
(EtOAc hexane 1 3) gave hemiacetal 26 (0.22 g,
W
W
W
W
hydrofuran derivative 24 (54 mg, 0.13 mmol, 57
z
＝
)
0.59 mmol, 82
z
) as colorless crystals, mp 158–
20
D
as colorless crystals, mp 73–74
9
C (iso-Pr2O). [
a
]
9
159 C (MeOH). [a] c 1.84, CHCl3). NMR
2D0＝＋32.1 (
－
＝
3.4 Hz, OH), 2.95
106 (
c
0.82, CHCl3). NMR dH (CDCl3): 2.51 (1H,
9.0, 3.9 Hz, OH),
H), 3.41 (3H, s,
8.8, 7.3 Hz, 5-H ), 3.76
11.2, 9.0, 5.4 Hz, C HOH), 3.98 (1H,
OH), 4.45 (1H, d,
HOCH3), 4.48 (1H, d, 6.4 Hz,
10.7 Hz, ArCHOM-
dH (CDCl3): 2.90 (0.7H, d,
J
m), 2.83 (1H, m), 3.08 (1H, dd,
J
＝
H
(1H, m), 3.20 (0.7H, m), 3.27 (0.3H, m), 3.95 (0.3H,
＝
＝
＝
H), 4.01(0.7H, dd, J
3.41 (1H, dd,
OCH3), 3.70 (1H, dd,
(1H, ddd,
J
8.8, 6.3 Hz, 5-
dd,
3.4 Hz, 8-H
8-
(1H, d,
br., OH), 4.96 (1H, d,
J
8.5, 3.9 Hz, 8-
H
9.3,
8.5, 6.4 Hz,
), 4.83
OCH2), 4.95–4.97 (0.3H,
6.8 Hz, ArC OCH2),
2.9 Hz, 4-H), 5.78 (0.3H, dd,
5.9, 5.4 Hz, 4-H), 5.96 (4H, s, OCH2O), 6.77–6.88
(5H, m, ArH), 7.04 (1H, s, ArH). NMR C (CDCl3):
＝
＝
J
H
H
), 4.05 (0.3H, dd,
J
J
＝
H
HH), 4.24 (0.7H, dd, J 9.3, 5.9 Hz, 8-HH
＝
＝
＝
7.3 Hz, ArC
ddd,
J
11.2, 7.8, 3.9 Hz, CH
H
J
J
H
J
＝
6.4 Hz, OC
H
J
＝
＝
H
＝
＝
＝
J
CH
H
OCH3), 4.71 (1H, d,
J
5.58 (0.7H, d,
J
＝
7.8 Hz, 2-H), 5.94 (2H, s,
OM), 4.74 (1H, d,
J
OCH2O), 5.98 (2H, s, OCH2O), 6.76 (4H, s, ArH),
6.79–6.83 (2H, s, ArH). NMR dC (CDCl3): 47.2,
52.6, 56.8, 60.3, 70.4, 82.8, 94.0, 101.0, 101.2, 106.3,
107.2, 108.1, 119.2, 121.6, 133.3, 136.3, 144.8. IR
d
53.1, 54.2, 57.3, 62.0, 70.5, 72.2, 79.6, 83.2, 83.7,
88.0, 98.3, 101.0, 101.6, 106.2, 106.3, 106.6, 107.0,
108.0, 108.1, 108.2, 119.1, 119.2, 119.5, 120.0,
134.7, 135.3, 136.0, 147.2, 147.3, 147.8, 148.0. IR
nmax (CHCl3): 3500, 2894, 1505, 1489, 1445, 1244,
1042 cm－
.
Anal. Found: C, 63.55; H, 6.11
z
.
nmax (CHCl3): 3400, 3013, 2890, 1505, 1489, 1447,
1
1248, 1042 cm－
.
Anal. Found: C, 64.48; H, 5.25
z.
1
Calcd. for C22H24O8: C, 63.45; H, 5.81
z.
Calcd. for C20H18O7: C, 64.86; H, 4.90
z.
(2 S,3 S,4 R )-4-[( S )-( Methoxymethoxy)(3,4-
m e t h y l e n e d i o x y p h e n y l ) m e t h y l ] - 2 - ( 3 , 4 -
methylenedioxyphenyl)-3-tetrahydrofurancarbalde-
hyde (25). A reaction mixture of alcohol 24 (0.61 g,
1.46 mmol) and PCC (0.35 g, 1.62 mmol), and MS
4A (0.1 g) in CH2Cl2 (20 ml) was stirred at room tem-
perature for 7 h before addition of dry ether. The
resulting mixture was ˆltered, and the resulting
(1 R,2 S,5 S,6S )-2,6-Bis(3,4-methylenediox-
yphenyl)-4-oxo-3,7-dioxabicyclo[3.3.0]octane (( )-
aptosimon 1). A reaction mixture of hemiacetal 26
(40 mg, 0.11 mmol) and PCC (26 mg, 0.12 mmol),
and MS 4A (10 mg) in CH2Cl2 (5 ml) was stirred at
room temperature for 3 h before addition of dry
ether. The mixture was ˆltered, and the resulting
＋

846
S. YAMAUCHI and M. YAMAGUCHI
new synthetic route to furofuranolid lignans via the
intramolecular mukaiyama reaction. J. Chem. Soc.
Perkin Trans. I, 185–190 (1992).
ˆltrate was concentrated. The residue was applied to
＝
silica gel column chromatography (EtOAc hexane
W
＋
1 3) to give ( )-aptosimon (1) (34 mg, 0.092 mmol,
W
6) Quideau, S., and Ralph, J., Synthesis of 4,8-bis(4-
hydroxy-3-methoxyphenyl)-3,7-dioxabicyclo[3.3.0]
octan-2-ones and determination of their relative con-
ˆguration via long-range proton couplings. J. Chem.
Soc. Perkin Trans. I, 653–659 (1993).
84
(lit.1) 123
＝＋
z
) as colorless crystals, mp 122–123
9
C (iso-Pr2O)
20
D
9
c
C). [ a]
a
]
2D0＝＋69.2 (
c
0.65, CHCl3), lit1) [
70 (
2.0, CHCl3). NMR dH (CDCl3): 3.20 (1H,
＝
m, 1-H), 3.42 (1H, dd,
J
9.0, 3.4 Hz, 5-H), 4.00
＝
＝
b-H), 4.32 (1H, dd, J
(1H, dd,
9.6, 6.8 Hz, 8
5.30 (1H, d,
J
9.6, 4.9 Hz, 8
-H), 5.28 (1H, d,
3.4 Hz, 6-H), 5.95 (2H, s, OCH2O),
7) Yoshida, S., Ogiku, T., Ohmizu, H., and Iwasaki,
T., New synthesis of 2,6-diaryl-4-oxo-3,7-dioxabicy-
＝
3.9 Hz, 2-H),
a
＝
J
J
±
clo[3.3.0]octanes: synthesis of ( )-styraxin. Synthe-
5.97 (2H, s, OCH2O), 6.75–6.79 (4H, m, ArH),
6.80–6.86 (2H, m, ArH). NMR dC (CDCl3): 49.9,
53.2, 72.6, 83.3, 84.3, 101.1, 101.4, 105.7, 105.9,
108.3, 108.5, 118.7, 118.8, 119.0, 133.0, 134.3,
sis, 1475–1480 (1997).
8) Brown, R. C. D., Bataille, C. J. R., Bruton, G.,
Hinks, J. D., and Swain, N. A., C-H insertion
approach to the synthesis of endo, exo-furofura-
nones: synthesis of (
and ( )-fargesin. J. Org. Chem., 66, 6719–6728
(2001).
)-asarinin, ( )-epimagnolin A,
± ±
147.2, 148.0, 148.3, 176.6. IR nmax (CHCl3): 3013,
±
2890, 1771, 1507, 1491, 1447, 1252, 1184, 1042 cm－
.
1
HRMS (FAB) m z (M＋ ): calcd. for C20H16O7,
W
9) MacRae, W. D., and Towers, G. H. N., Biological
activities of lignans. Phytochemistry, 23, 1207–1220
(1984).
10) Ayres, D. C., and Loike, J. D., Lignans. Cambridge
University Press, Cambridge (1990).
368.0896; found, 368.0901.
Acknowledgments
We measured the 400 MHz NMR data at
Advanced Instrumentation Center For Chemical
Analysis Ehime University. We thank the staŠ of this
center for the FAB measurements. We are grateful to
Marutomo Co. for ˆnancial support.
11) Yamauchi, S., Bando, S., and Kinoshita, Y., Synthe-
sis of 1,2-oxygenated 6-arylfurofuran lignan:
stereoselective synthesis of (1S,2S,5R,6S)-1-hydrox-
ysamin. Biosci. Biotechnol. Biochem., 66, 1495–1499
(2002).
12) Yamauchi, S., Machi, M., and Kinoshita, Y.,
－
Stereoselective syntheses of ( )-podorhizol lignan
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±
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