Stereocontrolled syntheses of (-)- And (+)-γ-diisoeugenol along with optically active eight stereoisomers of 7,8′-epoxy-8,7′-neolignan

Article abstract of DOI:10.1039/d1ob00008j

It was shown that reduction of the tertiary benzylic hydroxy group of (2R,3S,4R,5S)-3,5-bis(4-benzyloxy-3-methoxyphenyl)-2,4-dimethyltetrahydro-3-furanol 17 followed by the intramolecular Friedel-Crafts reaction gave exclusively indane with (7S,7′S,8R,8′R)-2,7′-cyclo-7,8′-neolignan structure 18 along with (7S,7′R,8S,8′R)-7,8′-epoxy-8,7′-neolignan structure 19. Indane 18 was converted to (-)-γ-diisoeugenol ((-)-4). On the other hand, (2S,3R,4R,5S)-3,5-bis(4-benzyloxy-3-methoxyphenyl)-2,4-dimethyltetrahydro-3-furanol 22 did not afford indane, but the tetrahydrofuran structure with (7S,7′S,8S,8′S)-7,8′-epoxy-8,7′-neolignan structure 23 and 7′-epi-23.

Full text of DOI:10.1039/d1ob00008j

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Stereocontrolled syntheses of (−)- and
(+)-γ-diisoeugenol along with optically active
Cite this: Org. Biomol. Chem., 2021,
19, 2168
eight stereoisomers of 7,8’-epoxy-8,7’-neolignan†
Received 4th January 2021,
Accepted 16th February 2021
Tatsuaki Takubo, Nao Kikuchi, Hisashi Nishiwaki and Satoshi Yamauchi
*
DOI: 10.1039/d1ob00008j
rsc.li/obc
It was shown that reduction of the tertiary benzylic hydroxy reduction and the intramolecular Friedel–Crafts reaction. It
group of (2R,3S,4R,5S)-3,5-bis(4-benzyloxy-3-methoxyphenyl)-2,4- would also be possible to obtain 7,8′-epoxy-8,7′-neolignan 2 by
dimethyltetrahydro-3-furanol 17 followed by the intramolecular controlling the reaction conditions. This article describes the
Friedel–Crafts reaction gave exclusively indane with (7S,7’S,8R,8’R)- first syntheses of (−)- and (+)-γ-diisoeugenol
4
and
2,7’-cyclo-7,8’-neolignan structure 18 along with (7S,7’R,8S,8’R)- (−)-γ-diisohomogenol 5,10 which are 2,7′-cyclo-7,8′-neolignan
7,8’-epoxy-8,7’-neolignan structure 19. Indane 18 was converted to bearing indane structures, along with some stereoisomers of
(−)-γ-diisoeugenol ((−)-4). On the other hand, (2S,3R,4R,5S)-3,5- 7,8′-epoxy-8,7′-neolignan 2.
bis(4-benzyloxy-3-methoxyphenyl)-2,4-dimethyltetrahydro-3-furanol
22 did not afford indane, but the tetrahydrofuran structure with (7S,7’
S,8S,8’S)-7,8’-epoxy-8,7’-neolignan structure 23 and 7’-epi-23.
Results and discussion
To construct the optically active 2,7′-cyclo-7,8′-neolignan or
7,8′-epoxy-8,7′-neolignan, 3-furanol with tertiary benzyl alco-
hols 17 and 22 were selected as substrates for reductions and
Introduction
intramolecular Friedel–Crafts reactions (Schemes 2 and 3).
Evans’ anti-aldol11 product 7 was converted to aldehyde 10.
Treatment of aldehyde 10 with vinylmagnesium bromide gave
allyl alcohol 11 (49%) and 3-epi-11 (14%). After the desilylation
of 11, the resulting diol 13 was subjected to iodoetherifica-
tion12 to give iodomethyltetrahydrofuran 14 (25%) and 2-epi-14
(65%). Irradiation at 5-H of 14 revealed the differential NOEs
of 2-CH2I (3%), 4-CH3 (7%), and 3-H (7%). In 2-epi-14, the
NOEs of 2-H/5-H (7%) and 5-H/4-CH3 (7%) were observed. The
reduction of iodide 14 followed by PCC oxidation gave fura-
none 16, in which the coupling constant between 2-H and 4-H
(1.5 Hz) was observed to confirm the stereochemistry of 2,4-cis.
The minor Grignard product 3-epi-11 was desilylated to give
diol 3-epi-13 (91% yield). Iodoetherification of 3-epi-13 gave
stereoselectively iodomethyltetrahydrofuran 3-epi-14 (88%
yield), whose configuration between 2- and 4-positions was
confirmed by differential NOE experiments (2-CH2I/5-H: 3%,
5-H/4-CH3: 7%). Furanol 3-epi-14 was transformed to furanone
16 (94% yield) by LiAlH4 reduction followed by PCC oxidation.
Furanol with tertiary benzyl alcohol 17 was stereoselectively
obtained (74%) by the treatment of ketone 16 with 4-benzy-
loxy-3-methoxyphenyllithium. The NOEs of OH/2-CH3 (4%),
OH/4-CH3 (4%), and OH/5-H (3%) were observed to confirm
the stereochemistry. Reduction of 17 using Et3SiH13 in the
The cytotoxicity, apoptosis, and inhibition of cyclooxygenase-
2 gene expression of 2,7′-cyclo-7,8′-neolignan (diisoeugenol)
(Scheme 1) have been reported.1 To clarify the effect of stereo-
chemistry on the biological activity, the synthesis of an opti-
cally pure compound is required. However, only the racemic
syntheses of 2,7′-cyclo-7,8′-neolignan have been reported to
date.2 On the other hand, 7,7′-epoxy-8,8′-lignan (2,5-bisaryl-3,4-
dimethyltetrahydrofuran) 6 possesses antimicrobial activity,3
plant growth regulatory activity,4 and cytotoxicity.5 The syn-
thetic research of the stereoisomers of 7,8′-epoxy-8,7′-neo-
lignan 2, which is the positional isomer of 6, would contribute
to the structure–activity relationship research of the neo-
lignan.6 Although the isolation,7 biological activity,8 and syn-
thetic study9 of 7,8′-epoxy-8,7′-neolignan 2 have been reported,
there are no reports on the syntheses of optically pure com-
pounds. We expected that the exposure of 3-furanol 3 bearing
tertiary benzyl alcohol to a Lewis acid and Et3SiH would give
the indane structure bearing 2,7′-cyclo-7,8′-neolignan structure
1, which is a synthetic intermediate to diisoeugenol 4, via
Graduate School of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime
790-8566, Japan. E-mail: syamauch@agr.ehime-u.ac.jp
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1ob00008j
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Scheme 1 Conversion of 3-furanol 3 to 2,7’-cyclo-7,8’-neolignan 1 (indane structure) and/or 7,8’-epoxy-8,7’-neolignan 2.
Scheme 2 Syntheses of (−)-γ-diisoeugenol ((−)-4) and (−)-γ-diisohomogenol ((−)-5) along with (7S,7’R,8S,8’R)-7,8’-epoxy-8,7’-neolignan (20). (a)
TIPSOTf, 2,6-lutidine, CH2Cl2, r.t., 1 h, 93% yield. (b) LiBH4, MeOH, THF, r.t., 1 h, 95% yield. (c) PCC, MS 4A, CH2Cl2, 0 °C, 16 h, 70% yield. (d)
Vinylmagnesium bromide, THF, r.t., 1 h, 11 (49%), 3-epi-11 (14%). (e) PDC, MS 4A, CH2Cl2, r.t., 16 h, 66% yield. (f) Method A, CeCl3·7H2O, NaBH4,
MeOH, THF, −60 °C, 3-epi-11 (37% yield), 11 (47% yield). Method B, DIBAL-H, toluene, −75 °C, 2 h, 3-epi-11 (54% yield), 11 (8% yield). (g) n-Bu4NF,
THF (from 11 to 13: 95% yield; from 3-epi-11 to 3-epi-13: 91% yield). (h) I2, NaHCO3, MeCN, 0 °C, 1 h (from 13 to 14: 25% yield, 2-epi-14: 65% yield;
from 3-epi-13 to 3-epi-14: 88% yield). (i) LiAlH4, THF, r.t., 30 min (from 14 to 15: 79% yield; from 3-epi-14 to 3-epi-15: 71% yield). ( j) PCC, MS 4A,
CH2Cl2, 0 °C, 16 h (from 15 to 16: 82% yield; from 3-epi-15 to 16: 94% yield). (k) 4-Benzyloxy-3-methoxyphenyllithium, THF, −70 °C, 1.5 h, 74%
yield. (l) Et3SiH, BF3·OEt2, CH2Cl2, 0–5 °C, 2 h, 18 (77% yield), 19 (8% yield). (m) (1) MsCl, Et3N, CH2Cl2, r.t., 1 h; (2) NaBH4, HMPA, 80 °C, 12 h, 48%
yield (2 steps). (n) H2, 5% Pd/C, EtOAc, r.t., 2 h (from 21 to (−)-4: 92% yield; from 19 to 20: 53% yield). (o) MeI, K2CO3, dibenzo-18-crown-6, MeCN,
reflux, 16 h (91% yield).
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Scheme 3 Reaction mechanism to prepare indane bearing 2,7’-cyclo-7,8’-neolignan structure 18 and preparation of stereoisomers of 7,8’-epoxy-
8,7’-neolignan (7’-epi-20, 24, 7’-epi-24). (a) Et3SiH, BF3·OEt2, CH2Cl2, −40 °C, 2 h, 22% yield, recovered 17 (74%). (b) H2, 5% Pd/C, EtOAc, r.t., 2 h (7’-
epi-20: 53% yield, 24: 100% yield, 7’-epi-24: 96% yield). (c) BF3·OEt2, CH2Cl2, 0–3 °C, 1 h, 76% yield. (d) LiAlH4, THF, r.t., 30 min, 74% yield. (e) PCC,
MS 4A, CH2Cl2, 0 °C, 16 h, 94% yield. (f) 4-Benzyloxy-3-methoxyphenyllithium, THF, −70 °C, 1.5 h, 94% yield. (g) ZnI2, NaBH3CN, 1,2-dichloroethane,
reflux, 4 h, 27% yield, recovered 22 (71%). (h) Et3SiH, BF3·OEt2, CH2Cl2, 0–3 °C, 30 min, 7’-epi-23 (57% yield), 23 (3% yield).
presence of BF3·OEt2 at 0 °C led to 2,7′-cyclo-7,8′-neolignan was opened by treatment with BF3·OEt2 to induce the benzylic
with indane skeleton 18 (77%) along with (7S,7′R,8S,8′R)-7,8′- cation, which stimulated the intramolecular Friedel–Crafts
epoxy-8,7′-neolignan 19 (8%). The reaction did not proceed by reaction. The aryl group bonded to the carbocation would be
employing
NaBH3CN
in
the
presence
of
ZnI2. placed at a farther position from the 9′-methyl group on the
(−)-γ-Diisoeugenol 4 was obtained from 18 by the reduction of SP2 plane. The π electron pair attacked the benzylic carbo-
the hydroxy group (48%, 2 steps) followed by hydrogenolysis cation to form the trans configuration. It could be assumed
(91%). The irradiation of 7-H appeared the NOEs of 7-H/7′-H that the intramolecular Friedel–Crafts reaction did not occur
(7%) and 7-H/9′-H (4%). The 1H-NMR datum was similar to in the case of stereoisomer 19 in Scheme 2 due to its stable
that of the literature.2b The 1H-NMR datum of 7,8-trans, 7′,8-trans, and 7′,8′-trans stereochemistry. The reac-
(−)-γ-diisohomogenol
5
obtained by methylation of tion of 19 with Et3SiH in the presence of BF3·OEt2 at 25 °C
(−)-γ-diisoeugenol 4 was also similar to that of the literature.10 resulted in the recovery of 19 (81%). 3-Franol with tertiary
On the other hand, hydrogenolysis of 19 afforded phenolic benzyl alcohol 22 was obtained from 2-epi-14, which was a
(7S,7′R,8S,8′R)-7,8′-epoxy-8,7′-neolignan 20 (53%). The NOEs of major product of the iodoetherification of diol 13, by the same
7-H/9′-H (3%), 7-H/9H (7%), and 7-H/7′-H (7%) confirmed this method described for the preparation of 17. The NOEs of HO/
stereochemistry. To obtain furanone 16 efficiently, allyl alcohol 2-CH3 (3%) and HO/4-H (3%) were observed in 22. Treatment
11 was isomerized to 3-epi-11 via ketone 12.
of 22 with ZnI2 and NaBH3CN14 afforded (7S,7′S,8S,8′S)-7,8′-
The proposed mechanism of the production of indane epoxy-8,7′-neolignan 23 in 23% yield along with the recovery of
bearing 2,7′-cyclo-7,8′-neolignan structure 18 is shown in 22 (71%). The approach of the hydride reagent to the resulting
Scheme 3. An explanation for the selective production of the 3-C carbocation would occur from the same side of the 7-aryl
indane structure involves the initial formation of 7′-epi-19, group, giving the 7,7′-trans form. On the other hand, appli-
which was not obtained under this reaction condition cation of 22 to Et3SiH and BF3·OEt2 at 0 °C gave 7′-epi-23 in
(0–5 °C); however, a lower reaction temperature (−40 °C) allows 57% yield. At this lower temperature, the attack of the hydride
the production of 7′-epi-19 in 22% yield along with the recovery reagent would occur from the opposite side of the 7-aryl group
of 17 (74%). The NOEs of 7-H/9′-H (3%) and 7-H/9-H (7%) in to give the 7,7′-cis form. Hydrogenolyses of 23 and 7′-epi-23
7′-epi-19 were observed. The tetrahydrofuran ring of 7′-epi-19 gave 24 (100%) and 7′-epi-24 (96%), respectively. The NOEs of
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Scheme 4 Synthesis of (+)-γ-diisoeugenol ((+)-4) along with 7,8’-epoxy-8,7’-neolignans (ent-20, ent-7’-epi-20, ent-24, ent-7’-epi-24).
7′-H/9′-H (7%) and 7-H/9-H (7%) in 24 and 7′-H/9-H (7%) and pounds follows the IUPAC rule. The nomenclature of the
7′-H/7-H (7%) in 7′-epi-24 confirmed their stereochemistries. lignan structure follows the literature.6
The indane structure was not obtained from tertiary benzyl
alcohol 22 by our entries.
The synthetic methods and data of 7–13 and 3-epi-13 are
shown in the ESI.†
(+)-γ-Diisoeugenol ((+)-4), ent-20, ent-7′-epi-20, ent-24, and
(2S,3R,4S,5S)-5-(4-Benzyloxy-3-methoxyphenyl)-2-iodomethyl-
ent-7′-epi-24 were synthesized from the enantiomer of Evnas’ 4-methyltetrahydro-3-furanol 3-epi-14. To
a suspension of
anti-aldol product ent-7 (Scheme 4). The enantiomeric excess diol 3-epi-13 (1.18 g, 3.59 mmol) and NaHCO3 (2.80 g,
of the synthesized compounds was determined as >99%ee 33.3 mmol) in MeCN (40 mL) was added iodine (8.10 g,
((−)- and (+)-diisoeugenol (4), 20, 7′-epi-20, ent-7′-epi-20, 24, 31.9 mmol) in MeCN (170 mL) at 0 °C. The resulting reaction
ent-24, 7′-epi-24) and 97%ee (ent-7′-epi-24, ent-20) by chiral mixture was stirred at room temperature for 1 h, and then sat.
column chromatography.
aq. Na2S2O3 and EtOAc were added. The organic solution was
separated, washed with brine, and dried (Na2SO4).
Concentration followed by silica gel column chromatography
(EtOAc/hexane = 1/3) gave iodomethyltetrahydrofuranol 3-epi-
14 (1.44 g, 3.16 mmol, 88%) as colorless crystals, mp
139–141 °C, [α]2D5 −31 (c 0.6, CHCl3). 1H NMR (400 MHz,
CDCl3) δ 1.02 (3H, d, J = 6.8 Hz, CH3), 1.95 (1H, br s, OH), 2.21
(1H, m, 4-H), 3.31 (1H, dd, J = 9.0, 4.9 Hz, 2-CHH-I), 3.38 (1H,
dd, J = 10.5, 9.0 Hz, 2-CHH-I), 3.90 (3H, s, OCH3), 4.45 (1H, m,
3-H), 4.53 (1H, ddd, J = 10.5, 4.9, 3.1 Hz, 2-H), 4.69 (1H, d, J =
10.5 Hz, 5-H), 5.14 (2H, s, OCH2Ph), 6.77 (1H, dd, J = 8.3, 1.8
Hz), 6.84 (1H, d, J = 8.3 Hz), 6.87 (1H, d, J = 1.8 Hz), 7.29 (1H,
m), 7.35 (2H, br dd, J = 7.6, 7.6 Hz), 7.42 (2H, br d, J = 7.6 Hz).
13C NMR (100 MHz, CDCl3) δ 2.59 (CH3), 9.59 (4-C), 48.0
(2-CH2-I), 56.0 (OCH3), 71.0 (OCH2Ph), 75.0 (2-C), 82.9 (5-C),
86.6 (3-C), 109.6, 113.7, 118.7, 127.2, 127.8, 128.5, 134.0, 137.1,
147.8, 149.7. FABMS: 455 (M + H)+. HRMS (FAB): calculated
C20H25O4I: 455.0721, found: 455.0716.
Conclusion
The stereoselective synthetic methods of optically pure
(−)-γ-diisoeugenol and (+)-γ-diisoeugenol bearing the 2,7′-
cyclo-7,8′-neolignan structure were explored by employing
reduction and the Friedel–Crafts reaction of tetra-substituted
3-furanol with tertiary benzylic alcohol. (7S,7′R,8S,8′R)-, (7S,7′
S,8S,8′R)-, (7S,7′S,8S,8′S)-, (7S,7′R,8S,8′S)-7,8′-Epoxy-8,7′-neo-
lignan and their enantiomers were also obtained by control-
ling the reaction conditions. The enantiomeric excess of these
compounds was determined as 97–100%ee.
Experimental
General experimental procedures
ent-3-epi-14. Colorless crystals, mp 140–142 °C, [α]2D5 +31 (c
0.3, CHCl3).
The melting point (mp) data are uncorrected. Optical rotations
(2S,3S,4S,5S)-5-(4-Benzyloxy-3-methoxyphenyl)-2-iodomethyl-
were measured on a JASCO P-2100 instrument. NMR data were 4-methyltetrahydro-3-furanol 14 and (2R,3S,4S,5S)-5-(4-benzy-
obtained using a JNM-EX400 spectrometer. EI and FABMS data loxy-3-methoxyphenyl)-2-iodomethyl-4-methyltetrahydro-3-furanol
were measured with a JMS-MS700V spectrometer. The silica 2-epi-14. 3-Franol 14 was obtained from 13 in 25% yield by
gel used was Silica Gel 60N (spherical, neutral, Kanto iodoetherification along with 2-epi-14 in 65% yield. 14: color-
1
Chemical, 40–50 μm). HPLC analysis was performed with less oil, [α]2D5 −28 (c 0.4, CHCl3). H NMR (400 MHz, CDCl3) δ
Shimadzu LC-6AD and SPD-6AV instruments. The chiral 1.06 (3H, d, J = 6.7 Hz, CH3), 2.19 (1H, m, 4-H), 2.25 (1H, br s,
column used for the HPLC analysis of enantiomeric excess was OH), 3.38–3.40 (2H, m, 2-CH2-I), 3.82 (1H, m, 3-H), 3.90 (3H, s,
CHIRALCEL AD-H (250 mm × 4.6 mm, i.d., 5 μm, DAICEL OCH3), 3.96 (1H, ddd, J = 6.3, 6.3, 5.0 Hz, 2-H), 4.49 (1H, d, J =
Chemical Industries, Ltd, Tokyo, Japan, 20% iso-PrOH/hexane, 10.3 Hz, 5-H), 5.15 (2H, s, OCH2Ph), 6.78 (1H, dd, J = 8.2, 1.8
1 mL min−1, detected at 283 nm). The numbering of com- Hz), 6.84 (1H, d, J = 8.2 Hz), 6.92 (1H, d, J = 1.8 Hz), 7.29 (1H,
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m), 7.35 (2H, m), 7.42 (2H, m). 13C NMR (100 MHz, CDCl3) δ 118.7, 127.2, 127.7, 128.5, 134.6, 137.1, 147.7, 149.7; FABMS
8.96 (CH3), 13.2 (4-C), 50.0 (2-CH2-I), 56.0 (OCH3), 71.0 329 (M + H)+. Anal. found: C 73.26%, H 7.34%; calcd for
(OCH2Ph), 81.7 (2-C), 83.1 (5-C), 85.6 (3-C), 109.7, 113.7, 119.0, C20H24O4: C 73.15%, H 7.37%.
127.2, 127.8, 128.5, 133.1, 137.0, 148.0, 149.8. FABMS 455 (M +
H)+. Anal. found: C 52.77%, H 5.42%; calcd for C20H23O4I: C
ent-15. Colorless oil, [α]2D5 −0.2 (c 0.2, CHCl3).
(2R,4R,5S)-5-(4-Benzyloxy-3-methoxyphenyl)-2,4-dimethyl-3
52.88%, H 5.10%. 2-epi-14: colorless crystals, mp 112–113 °C (2H)-furanone 16. A reaction mixture of alcohol 3-epi-15
(EtOAc/hexane = 1/1), [α]2D5 +3.9 (c 0.8, CHCl3). 1H NMR (0.45 g, 1.37 mmol), PCC (0.35 g, 1.62 mmol), and MS 4A
(400 MHz, CDCl3) δ 1.10 (3H, d, J = 6.9 Hz, CH3), 2.06 (1H, br (0.5 g) in CH2Cl2 (20 mL) was stirred at 0 °C for 16 h. After the
s, OH), 2.13 (1H, m, 4-H), 3.35 (1H, dd, J = 9.8, 5.6 Hz, addition of ether, the mixture was filtered. The filtrate was con-
2-CHH-I), 3.44 (1H, dd, J = 9.8, 7.5 Hz, 2-CHH-I), 3.90 (3H, s, centrated and the residue was subjected to silica gel column
OCH3), 4.10 (1H, m, 3-H), 4.16 (1H, ddd, J = 7.4, 5.5, 5.5 Hz, chromatography (EtOAc/hexane = 1/4) to give ketone 16 (0.42 g,
2-H), 4.29 (1H, d, J = 8.1 Hz, 5-H), 5.14 (2H, s, OCH2Ph), 6.82 1.29 mmol, 94%) as a colorless oil, [α]2D5 −52 (c 1.6, CHCl3). 1H
(2H, s), 7.03 (1H, s), 7.28 (1H, m), 7.35 (2H, m), 7.42 (2H, d, J = NMR (400 MHz, CDCl3) δ 1.11 (3H, d, J = 7.0 Hz, 4-CH3), 1.33
7.2 Hz). 13C NMR (100 MHz, CDCl3) δ 3.21 (CH3), 15.3 (4-C), (3H, d, J = 7.3 Hz, 2-CH3), 2.45 (1H, ddq, J = 10.1, 7.0, 1.5 Hz,
50.3 (2-CH2-I), 56.0 (OCH3), 70.9 (OCH2Ph), 79.4 (2-C), 80.2 4-H), 3.91 (3H, s, OCH3), 4.44 (1H, dq, J = 7.0, 1.5 Hz, 2-H),
(5-C), 86.5 (3-C), 109.9, 113.6, 118.7, 127.2, 127.7, 128.5, 133.5, 4.67 (1H, d, J = 10.1 Hz, 5-H), 5.16 (2H, s, OCH2Ph), 6.86–6.87
137.0, 147.8, 149.7. FABMS 455 (M + H)+. HRMS (FAB): calcu- (2H, m), 7.01 (1H, d, J = 1.5 Hz), 7.28 (1H, m), 7.35 (2H, dd, J =
lated C20H25O4I: 455.0721, found: 455.0719.
7.1, 7.1 Hz), 7.43 (2H, d, J = 7.1 Hz). 13C NMR (100 MHz,
CDCl3) δ 10.8 (4-CH3), 16.2 (2-CH3), 50.1 (4-H), 56.3 (OCH3),
ent-14. Colorless oil, [α]2D5 +30 (c 0.9, CHCl3).
ent-2-epi-14. Colorless crystals, mp 112–114 °C, [α]D25 −7 (c 71.2 (OCH2Ph), 76.7 (2-C), 83.5 (5-C), 109.7, 114.0, 119.0,
0.6, CHCl3).
127.4, 128.1, 128.7, 132.8, 137.2, 148.5, 150.2, 218.0 (CvO).
(2R,3R,4S,5S)-5-(4-Benzyloxy-3-methoxyphenyl)-2,4-dimethyl- FABMS: 327 (M + H)+. HRMS (FAB): calculated C20H23O4:
tetrahydro-3-furanol 3-epi-15. To an ice-cooled suspension of 327.1596, found: 327.1589. Alcohol 15 was converted to ketone
LiAlH4 (0.19 g, 5.01 mmol) in THF (5 mL) was added a solution 16 by PCC oxidation in 82% yield.
of iodide 3-epi-14 (1.14 g, 2.50 mmol) in THF (10 mL). After
ent-16. Colorless oil, [α]2D5 +60 (c 0.7, CHCl3).
the reaction mixture was stirred at room temperature for
(2R,3S,4R,5S)-3,5-Bis(4-benzyloxy-3-methoxyphenyl)-2,4-di-
30 min, sat. aq. MgSO4 and K2CO3 were added. The mixture methyltetrahydro-3-furanol 17. To a solution of 1-benzyloxy-4-
was filtered, and then the filtrate was concentrated. The bromo-2-methoxybenzene (1.18 g, 4.03 mmol) in THF (10 mL)
residue was subjected to silica gel column chromatography was added n-BuLi (1.92 mL, 2.7 M in hexane, 5.18 mmol) at
(EtOAc/hexane = 1/1) to give 3-epi-15 (0.58 g, 1.77 mmol, 71%) −70 °C. The reaction solution was stirred at −70 °C for 10 min,
as colorless crystals, mp 100–102 °C, [α]2D5 +9 (c 0.3, CHCl3). 1H and then a solution of ketone 16 (0.53 g, 1.62 mmol) in THF
NMR (400 MHz, CDCl3) δ 1.06 (3H, d, J = 6.8 Hz, 4-CH3), 1.33 (10 mL) was added at −70 °C. After stirring at −70 °C for 1.5 h,
(3H, d, J = 6.4 Hz, 2-CH3), 1.63 (1H, br s, OH), 2.22 (1H, ddq, J sat. aq. NH4Cl and EtOAc were added. The organic solution
= 10.2, 6.8, 3.8 Hz, 4-H), 3.90 (3H, s, OCH3), 4.07 (1H, m, 3-H), was separated and dried (Na2SO4). Concentration followed by
4.40 (1H, dq, J = 6.4, 3.0 Hz, 2-H), 4.58 (1H, d, J = 10.2 Hz, silica gel column chromatography (EtOAc/hexane = 1/3) gave
5-H), 5.14 (2H, s, OCH2Ph), 6.78 (1H, dd, J = 8.2, 1.9 Hz), 6.84 3-furanol 17 (0.65 g, 1.20 mmol, 74%) as a colorless oil, [α]D25
(1H, d, J = 8.2 Hz), 6.89 (1H, d, J = 1.9 Hz), 7.29 (1H, m), 7.35 +27 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 0.89 (3H, d, J =
(2H, br dd, J = 7.6, 6.9 Hz), 7.43 (2H, br d, J = 7.0 H). 13C NMR 6.8 Hz, 4-CH3), 1.19 (3H, d, J = 6.3 Hz, 2-CH3), 1.90 (1H, s,
(100 MHz, CDCl3) δ 10.1 (4-CH3), 14.8 (2-CH3), 48.5 (4-C), 56.0 OH), 2.52 (1H, dq, J = 9.8, 6.8 Hz, 4-H), 3.91 (3H, s, OCH3),
(OCH3), 71.0 (OCH2Ph), 76.7 (2-C), 79.0 (5-C), 84.9 (3-C), 109.7, 3.92 (3H, s, OCH3), 4.44 (1H, q, J = 6.4 Hz, 2-H), 4.71 (1H, d, J =
113.9, 118.5, 127.2, 127.7, 128.5, 135.3, 137.2, 147.6, 149.7. 9.8 Hz, 5-H), 5.14 (2H, s, OCH2Ph), 5.15 (2H, s, OCH2Ph), 6.86
FABMS 329 (M + H)+. HRMS (FAB): calculated C20H25O4: (4H, s), 6.95 (1H, s), 7.07 (1H, s), 7.28 (2H, m), 7.34 (2H, dd, J =
329.1753, found: 329.1760.
7.2, 1.5 Hz), 7.36 (2H, dd, J = 7.2, 1.7 Hz), 7.43 (4H, d, J = 7.2
ent-3-epi-15. [α]2D5 −9 (c 0.7, CHCl3), colorless crystals, mp Hz). 13C NMR (100 MHz, CDCl3) δ 8.7 (4-CH3), 12.9 (2-CH3),
100–102 °C.
53.5 (4-C), 56.06 (OCH3), 56.12 (OCH3), 70.9 (OCH2Ph), 71.0
(2R,3S,4S,5S)-5-(4-Benzyloxy-3-methoxyphenyl)-2,4-dimethyl- (OCH2Ph), 83.1 (2-C), 83.7 (5-C), 85.2 (3-C), 109.6, 109.7, 113.5,
tetrahydro-3-furanol 15. 79% yield from 14, colorless oil, [α]2D5 113.9, 117.2, 118.2, 127.2, 127.7, 127.8, 128.47, 128.50, 133.2,
1
+0.2 (c 0.4, CHCl3). H NMR (400 MHz, CDCl3) δ 1.06 (3H, d, J 135.3, 137.0, 137.1, 147.3, 147.6, 149.4, 149.7. FABMS: 541 (M
= 6.5 Hz, 4-CH3), 1.35 (3H, d, J = 6.1 Hz, 2-CH3), 2.01 (1H, br d, + H)+. HRMS (FAB): calculated C34H37O6: 541.2591, found:
J = 5.1 Hz, OH), 2.06 (1H, m, 4-H), 3.53 (1H, m, 3-H), 3.90 (3H, 541.2594.
s, OCH3), 4.03 (1H, dq, J = 6.5, 6.1 Hz, 2-H), 4.43 (1H, d, J = 9.8
Hz, 5-H), 5.14 (2H, s, OCH2Ph), 6.78 (1H, dd, J = 8.1, 1.6 Hz),
ent-17. Colorless oil, [α]2D5 −27 (c 1.1, CHCl3).
(1S,2R,3S)-6-Benzyloxy-1-(4-benzyloxy-3-methoxyphenyl)-
6.83 (1H, d, J = 8.1 Hz), 6.93 (1H, d, J = 1.6 Hz), 7.28 (1H, m), 3-((R)-1-hydroxyeth-1-yl)-5-methoxy-2-methylindane, (7S,7′
7.35 (2H, m), 7.42 (2H, d, J = 7.5 Hz). 13C NMR (100 MHz, S,8R,8′R)-4,4′-dibenzyloxy-3′,5-dimethoxy-2,7′-cyclo-7,8′-neo-
CDCl3) δ 13.7 (4-CH3), 19.1 (2-CH3), 50.2 (4-C), 55.9 (OCH3), lignan-8-ol 18 and (2S,3S,4R,5R)-2,4-bis(4-benzyloxy-3-meth-
71.0 (OCH2Ph), 79.8 (2-C), 84.1 (5-C), 84.9 (3-C), 109.6, 113.6, oxyphenyl)-3,5-dimethyltetrahydrofuran,
(7S,7′R,8S,8′R)-
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4,4′-dibenzyloxy-3,3′-dimethoxy-7,8′-epoxy-8,7′-neolignan 19. m), 742–7.47 (4H, m). 13C NMR (100 MHz, CDCl3) δ 13.0 (9-C),
To a solution of 3-furanol 17 (0.16 g, 0.30 mmol) and Et3SiH 16.8 (9′-C), 29.7 (8-C), 48.8 (7′-C), 55.6 (OCH3), 56.1 (OCH3),
(0.46 mL, 2.88 mmol) in CH2Cl2 (12 mL) was added BF3·OEt2 71.1 (OCH2Ph × 2), 79.2 (8′-C), 86.1 (7-C), 109.6, 113.6, 113.9,
(25 μL, 0.20 mmol) at 0 °C. After the reaction solution was 114.0, 118.0, 122.4, 127.2, 127.3, 127.8, 128.5, 131.0, 136.7,
stirred at 0–5 °C for 2 h, sat. aq. NaHCO3 was added. The 137.25, 137.32, 146.8, 147.5, 149.2, 149.7. FABMS 525 (M + H)+.
organic solution was separated and dried (Na2SO4). HRMS (FAB): calculated C34H37O5: 525.2641, found: 525.2639.
Concentration followed by silica gel column chromatography
ent-7′-epi-19. Colorless oil, [α]2D5 −39 (c 0.1, CHCl3).
(EtOAc/hexane = 1/3) gave 18 (0.12 g, 0.23 mmol, 77%) as a
Conversion of 7′-epi-19 to indane 18. To a solution of 7′-epi-
colorless oil, [α]2D5 −75 (c 1.8, CHCl3), and 19 (12 mg, 19 (42 mg, 0.078 mmol) in CH2Cl2 (5 mL) was added BF3·OEt2
0.022 mmol, 8%) as a colorless oil, [α]2D5 −7 (c 0.2, CHCl3). 18: (10 μL, 0.079 mmol) at 0 °C, and then the reaction solution
1H NMR (400 MHz, CDCl3) δ 1.23 (3H, d, J = 6.6 Hz, 9′-H), 1.29 was stirred at 0–3 °C for 1 h before the addition of sat. aq.
(3H, d, J = 6.4 Hz, 9-H), 1.67 (1H, br s, OH), 2.12 (1H, m, 8′-H), NaHCO3 and CH2Cl2. The organic solution was separated and
2.83 (1H, dd, J = 9.6, 5.9 Hz, 7-H), 3.65 (1H, d, J = 8.0 Hz, 7′-H), dried (Na2SO4). Concentration followed by silica gel column
3.76 (3H, s, OCH3), 3.87 (3H, s, OCH3), 4.08 (1H, m, 8-H), 4.95 chromatography (EtOAc/hexane
= 1/3) gave 18 (31 mg,
(1H, d, J = 12.2 Hz, OCHHPh), 5.00 (1H, d, J = 12.2 Hz, 0.059 mmol, 76%).
OCHHPh), 5.14 (2H, s, OCH2Ph), 6.46 (1H, s), 6.58 (1H, dd, J =
(2S,3S,4R,5R)-2,4-Bis(4-hydroxy-3-methoxyphenyl)-3,5-dimethyl-
8.2, 1.9 Hz), 6.62 (1H, d, J = 1.9 Hz), 6.80 (1H, d, J = 8.2 Hz), tetrahydrofuran, (7S,7′R,8S,8′R)-3,3′-dimethoxy-7,8′-epoxy-8,7′-neo-
6.99 (1H, s), 7.21–7.29 (4H, m), 7.30–7.38 (4H, m), 7.45 (2H, d, lignan-4,4′-diol 20. A reaction mixture of benzyl ether 19
J = 7.1 Hz). 13C NMR (100 MHz, CDCl3) δ 19.6 (9′-C), 21.4 (9-C), (12 mg, 0.022 mmol) and 5% Pd/C (20 mg) in EtOAc (10 mL)
47.4 (8′-C), 55.9 (OCH3), 56.2 (OCH3), 58.0 (7-C), 58.5 (7′-C), was stirred under a H2 atmosphere at room temperature for
70.5 (8-C), 70.8 (OCH2Ph), 71.0 (OCH2Ph), 108.3, 110.7, 111.7, 2 h, and then the mixture was filtered. After concentration of
113.7, 120.4, 127.2, 127.3, 127.6, 127.7, 128.3, 128.4, 136.0, the filtrate, the residue was subjected to silica gel column
137.0, 137.3, 138.0, 138.2, 146.7, 147.7, 148.9, 149.5. FABMS chromatography (EtOAc/hexane = 1/3) to give 20 (4 mg,
525 (M + H)+. HRMS (FAB): calculated C34H37O5: 525.2641, 0.012 mmol, 53%) as a colorless oil, [α]D25 +38 (c 0.05, CHCl3).
1
found: 525.2635. 19: H NMR (400 MHz, CDCl3) δ 0.92 (3H, d, 1H NMR (400 MHz, CDCl3) δ 0.93 (3H, d, J = 6.5 Hz, 9-H), 1.29
J = 6.4 Hz, 9-H), 1.29 (3H, d, J = 6.0 Hz, 9′-H), 2.25 (1H, m, (3H, d, J = 6.0 Hz, 9′-H), 2.24 (1H, m, 8-H), 2.52 (1H, dd, J =
8-H), 2.52 (1H, dd, J = 11.0, 9.5 Hz, 7′-H), 3.89 (3H, s, OCH3), 11.1, 9.5 Hz, 7′-H), 3.90 (3H, s, OCH3), 3.94 (3H, s, OCH3), 4.27
3.93 (3H, s, OCH3), 4.27 (1H, m, 8′-H), 4.54 (1H, d, J = 9.4 Hz, (1H, m, 8′-H), 4.54 (1H, d, J = 9.5 Hz, 7-H), 5.58 (1H, br s, OH),
7-H), 5.14 (2H, s, OCH2Ph), 5.16 (2H, s, OCH2Ph), 6.71 (1H, d, 5.59 (1H, br s, OH), 6.70 (1H, d, J = 1.8 Hz), 6.75 (1H, dd, J =
J = 1.7 Hz), 6.74 (1H, dd, J = 8.2, 1.7 Hz), 6.85 (1H, d, J = 8.2 8.2, 1.8 Hz), 6.88 (1H, d, J = 8.2 Hz), 6.91 (2H, s), 6.95 (1H, s).
Hz), 6.87 (2H, s), 6.99 (1H, s), 7.28–7.31 (2H, m), 7.34–7.38 13C NMR (100 MHz, CDCl3) δ 14.1 (9-C), 20.0 (9′-C), 51.2 (8-C),
(4H, m), 7.41–7.45 (4H, m); 13C NMR (100 MHz, CDCl3) δ 14.2 56.0 (OCH3 × 2), 62.0 (7′-C), 81.8 (8′-C), 87.1 (7-C), 108.7, 110.1,
(9′-C), 20.0 (9-C), 51.1 (8-C), 56.1 (OCH3 × 2), 61.9 (7′-C), 71.1 114.2, 114.5, 119.3, 120.6, 131.0, 134.0, 144.6, 145.1, 146.55,
(OCH2Ph × 2), 81.8 (8′-C), 87.0 (7-C), 110.0, 111.6, 114.0, 114.1, 146.62; EIMS m/z (%): 344 (M+, 33), 300 (100), 285 (56), 137
118.5, 120.0, 127.3, 127.8, 128.5, 132.3, 135.2, 137.2, 147.2, (80). HRMS (EI): calculated C20H24O5: 344.1624, found:
147.7, 149.7; FABMS 525 (M + H)+. HRMS (FAB): calculated 344.1631. >99%ee (AD-H, 254 nm, 20% 2-propanol/hexane,
C34H37O5: 525.2641, found: 525.2637.
1 mL min−1, tR 20.6 min).
ent-18. Colorless oil, [α]2D5 +75 (c 0.2, CHCl3).
ent-20. Colorless oil, [α]2D5 −40 (c 0.04, CHCl3). 97%ee
(AD-H, 254 nm, 20% 2-propanol/hexane, 1 mL min−1, tR
33.8 min).
ent-19. Colorless oil, [α]2D5 +7 (c 0.2, CHCl3).
(2S,3S,4S,5R)-2,4-Bis(4-benzyloxy-3-methoxyphenyl)-3,5-dimethyl-
tetrahydrofuran, (7S,7′S,8S,8′R)-(4,4′-dibenzyloxy-3,3′-dimethoxy-7,8′-
(2S,3S,4S,5R)-2,4-Bis(4-hydroxy-3-methoxyphenyl)-3,5-dimethyl-
epoxy-8,7′-neolignan 7′-epi-19. To a solution of 3-furanol 17 tetrahydrofuran,
(7S,7′S,8S,8′R)-3,3′-dimethoxyl-7,8′-epoxy-8,7′-
(70 mg, 0.13 mmol) and Et3SiH (0.21 mL, 1.30 mmol) in neolignan-4,4′-diol 7′-epi-20. 53% yield, colorless crystals, mp
CH2Cl2 (5 mL) was added BF3·OEt2 (11 μL, 0.091 mmol) at 84–85 °C, [α]2D5 +84 (c 0.1, CHCl3). 1H NMR (400 MHz, CDCl3) δ
−40 °C. After the reaction solution was stirred at −40 °C for 0.72 (3H, d, J = 6.8 Hz, 9-H), 1.20 (3H, d, J = 6.4 Hz, 9′-H), 2.58
2 h, sat. aq. NaHCO3 was added. The organic solution was sep- (1H, m, 8-H), 3.15 (1H, dd, J = 8.4, 5.3 Hz, 7′-H), 3.91 (3H, s,
arated and dried (Na2SO4). Concentration followed by silica gel OCH3), 3.92 (3H, s, OCH3), 4.62 (1H, d, J = 9.7 Hz, 7-H), 4.71
column chromatography (EtOAc/hexane = 1/3) gave 7′-epi-19 (1H, m, 8′-H), 5.56 (1H, s, OH), 5.57 (1H, s, OH), 6.72 (1H, dd, J
(15 mg, 0.029 mmol, 22%) as a colorless oil, [α]2D5 +34 (c 0.3, = 8.1, 1.5 Hz), 6.78 (1H, d, J = 1.5 Hz), 6.85 (1H, dd, J = 8.1, 1.7
CHCl3). 3-Furanol 17 (52 mg, 0.096 mmol, 74%) was recovered. Hz), 6.88–6.90 (3H, m). 13C NMR (100 MHz, CDCl3) δ 12.9
1H NMR (400 MHz, CDCl3) δ 0.71 (3H, d, J = 6.8 Hz, 9-H), 1.19 (9-C), 16.9 (9′-C), 48.8 (8-C), 55.7 (7′-C), 55.9 (OCH3), 56.0
(3H, d, J = 6.5 Hz, 9′-H), 2.58 (1H, m, 8-H), 3.15 (1H, dd, J = 6.5, (OCH3), 79.2 (8′-C), 86.2 (7-C), 108.3, 112.4, 114.0, 114.2, 118.8,
4.4 Hz, 7′-H), 3.90 (3H, s, OCH3), 3.92 (3H, s, OCH3), 4.62 (1H, 123.2, 129.7, 135.4, 144.2, 144.9, 146.2, 146.6. EIMS m/z (%):
d, J = 9.7 Hz, 7-H), 4.71 (1H, m, 8′-H), 5.15 (4H, s, OCH2Ph), 344 (M+, 16), 300 (100), 284 (45). HRMS (EI): calculated
6.71 (1H, dd, J = 8.2, 2.0 Hz), 6.82–6.87 (3H, m), 6.87 (1H, d, J = C20H24O5: 344.1624, found: 344.1613. >99%ee (AD-H, 254 nm,
8.2 Hz), 6.94 (1H, d, J = 1.5 Hz), 7.30 (2H, m), 7.33–7.39 (4H, 20% 2-propanol/hexane, 1 mL min−1, tR 9.8 min).
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ent-7′-epi-20. Colorless oil, [α]2D5 −84 (c 0.1, CHCl3) >99%ee
ent-4 ((+)-diisoeugenol). Colorless crystals, mp 98–100 °C,
(AD-H, 254 nm, 20% 2-propanol/hexane, 1 mL min−1, tR [α]D25 +24 (c 0.1, CHCl3), >99%ee (AD-H, 254 nm, 5% 2-propa-
18.7 min).
nol/hexane, 1 mL min−1, tR 38.3 min).
(1S,2S,3S)-6-Benzyloxy-1-(4-benzyloxy-3-methoxyphenyl)-3-ethyl-
(1S,2S,3S)-1-Ethyl-5,6-dimethoxy-3-(3,4-dimethoxyphenyl)-2-
5-methoxy-2-methylindane,
(7S,7′S,8′S)-4,4′-dibenzyloxy-3′,5- methylindane, (7S,7′S,8′S)-3′,4,4′,5-tetramethoxy-2,7′-cyclo-7,8′-
dimethoxy-2,7′-cyclo-7,8′-neolignan 21. To an ice-cooled solution neolignan, (−)-γ-diisohomogenol 5. A reaction mixture of
of alcohol 18 (96 mg, 0.18 mmol) and Et3N (80 μL, 0.57 mmol) (−)-γ-diisoeugenol (4) (73 mg, 0.22 mmol), MeI (1.00 mL,
in CH2Cl2 (5 mL) was added MsCl (40 μL, 0.52 mmol). The 16.1 mmol), K2CO3 (0.12 g, 0.87 mmol), and dibenzo-18-
reaction mixture was stirred at room temperature for 1 h, and crown-6 (10 mg) in MeCN (20 mL) was heated under reflux for
then H2O and CH2Cl2 were added. The organic solution was 16 h before filtration. Concentration of the filtrate followed by
separated and dried (Na2SO4). Concentration followed by silica silica gel column chromatography (EtOAc/hexane = 1/3) gave
gel column chromatography gave crude mesylate. A reaction (−)-γ-diisohomogenol (5) (73 mg, 0.20 mmol, 91%) as a color-
1
mixture of crude mesylate and NaBH4 (0.10 g, 2.64 mmol) in less oil, [α]2D5 −83 (c 0.1, CHCl3). H NMR (400 MHz, CDCl3) δ
HMPA (2 mL) was stirred at 80 °C for 12 h before the addition 1.01 (3H, t, J = 7.5 Hz, 9-H), 1.17 (3H, d, J = 6.6 Hz, 9′-H), 1.79
of sat. aq. NH4Cl and EtOAc. The organic solution was separ- (1H, m, 8-HH), 1.90 (1H, m, 8-HH), 2.00 (1H, m, 8′-H), 2.71
ated and dried (Na2SO4). Concentration followed by silica gel (1H, m, 7-H), 3.65 (1H, d, J = 9.3 Hz, 7′-H), 3.72 (3H, s, OCH3),
column chromatography (EtOAc/hexane = 1/4) gave 21 (44 mg, 3.82 (3H, s, OCH3), 3.89 (3H, s, OCH3), 3.90 (3H, s, OCH3),
0.087 mmol, 48%, 2 steps) as a colorless oil, [α]2D5 −63 (c 0.8, 6.40 (1H, s), 6.68 (1H, d, J = 2.1 Hz), 6.77 (1H, dd, J = 8.1, 2.1
CHCl3). 1H NMR (400 MHz, CDCl3) δ 1.00 (3H, t, J = 7.5 Hz, Hz), 6.77 (1H, s), 6.85 (1H, d, J = 8.1 Hz). 13C NMR (100 MHz,
9-H), 1.15 (3H, d, J = 6.6 Hz, 9′-H), 1.78 (1H, m, 8-CHH), 1.87 CDCl3) δ 10.9 (9-C), 17.7 (9′-C), 25.0 (8-C), 51.1 (8′-C), 51.7
(1H, m, 8-CHH), 1.97 (1H, m, 8′-H), 2.69 (1H, ddd, J = 8.9, 5.4, (7-C), 55.9 (OCH3 × 2), 56.0 (OCH3), 56.1 (OCH3), 58.6 (7′-C),
5.4 Hz, 7-H), 3.59 (1H, d, J = 9.3 Hz, 7′-H), 3.77 (3H, s, OCH3), 106.5, 107.8, 111.1, 111.5, 120.8, 137.3, 138.1, 138.4, 147.6,
3.89 (3H, s, OCH3), 4.94 (1H, d, J = 12.2 Hz, OCHHPh), 4.99 148.2, 148.3, 149.0. EIMS m/z (%): 356 (M+, 95), 327 (100).
(1H, d, J = 12.2 Hz, OCHHPh), 5.15 (2H, s, OCH2Ph), 6.44 (1H, HRMS (EI): calculated C22H28O4: 356.1988, found: 356.1985.
s), 6.61–6.63 (2H, m), 6.77 (1H, s), 6.82 (1H, d, J = 8.7 Hz),
(2S,3R,4R,5S)-3,5-Bis(4-benzyloxy-3-methoxyphenyl)-2,4-di-
7.24–7.26 (2H, m), 7.28–7.39 (6H, m), 7.46 (2H, d, J = 7.3 Hz). methyltetrahydro-3-furanol 22. 2-epi-15 was obtained by
13C NMR (100 MHz, CDCl3) δ 11.0 (9-C), 17.6 (9′-C), 24.9 (8-C), LiAlH4 reduction of 2-epi-14 in 74% yield as colorless crystals,
51.0 (8′-C), 51.6 (7-C), 56.0 (OCH3), 56.3 (OCH3), 58.4 (7′-C), mp 74–75 °C, [α]2D5 +17 (c 0.7, CHCl3). 1H NMR (400 MHz,
71.0 (OCH2Ph × 2), 107.1, 110.7, 111.9, 113.7, 120.7, 127.2, CDCl3) δ 1.11 (3H, d, J = 6.9 Hz, 4-CH3), 1.34 (3H, d, J = 6.4 Hz,
127.4, 127.6, 127.7, 128.3, 128.5, 137.2, 137.4, 137.7, 138.0, 2-CH3), 1.78 (1H, br s, OH), 2.06 (1H, m, 4-H), 3.86 (1H, m,
139.1, 146.7, 147.2, 149.0, 149.5. FABMS 509 (M + H)+. HRMS 3-H), 3.89 (3H, s, OCH3), 4.05 (1H, dq, J = 6.9, 5.0 Hz, 2-H),
(FAB): calculated C34H37O4: 509.2692, found: 509.2688.
ent-21. Colorless oil, [α]2D5 +63 (c 0.1, CHCl3).
(1S,2S,3S)-1-Ethyl-5-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-
4.21 (1H, d, J = 7.7 Hz, 5-H), 5.14 (2H, s, OCH2Ph), 6.82–6.83
(2H, m), 6.97 (1H, s), 7.28 (1H, s), 7.35 (2H, m), 7.42 (2H, m).
13C NMR (100 MHz, CDCl3) δ 14.6 (4-CH3), 15.7 (2-CH3), 50.9
6-methoxy-2-methylindane,
(7S,7′S,8′S)-3′,5-dimethoxy-2,7′- (4-C), 55.9 (OCH3), 71.0 (OCH2Ph), 77.0 (2-C), 80.4 (5-C), 86.4
cyclo-7,8′-neolignan-4,4′-diol, (−)-γ-diisoeugenol 4. A reaction (3-C), 110.0, 113.7, 118.7, 127.2, 127.7, 128.4, 134.2, 137.1,
mixture of benzyl ether 21 (40 mg, 0.079 mmol) and 5% Pd/C 147.7, 149.6; FABMS 328 (M+). Anal. found: C 73.31%, H
(50 mg) in EtOAc (10 mL) was stirred under H2 gas at room 7.42%; calcd for C20H24O4: C 73.15%, H 7.37%. ent-2-epi-15.
temperature for 2 h before filtration. The filtrate was concen- Colorless crystals, mp 73–74 °C, [α]2D5 −18 (c 0.5, CHCl3). 2-epi-
trated, and then the residue was subjected to silica gel column 16 was obtained by PCC oxidation of 2-epi-15 at 0 °C in 94%
chromatography
(EtOAc/hexane
=
1/1)
to
give yield as colorless crystals, mp 98–99 °C; [α]2D5 −63 (c 0.4,
1
(−)-γ-diisoeugenol (4) (24 mg, 0.073 mmol, 92%) as colorless CHCl3). H NMR (400 MHz, CDCl3) δ 1.11 (3H, d, J = 6.9 Hz,
crystals, mp 100–103 °C, [α]2D5 −24 (c 0.4, CHCl3). 1H NMR 4-CH3), 1.45 (3H, d, J = 6.8 Hz, 2-CH3), 2.36 (1H, dq, J = 10.4,
(400 MHz, CDCl3) δ 1.01 (3H, t, J = 7.4 Hz, 9-H), 1.15 (3H, d, J = 6.9 Hz, 4-H), 3.92 (3H, s, OCH3), 3.98 (1H, q, J = 6.8 Hz, 2-H),
6.5 Hz, 9′-H), 1.78 (1H, m, 8-HH), 1.88 (1H, m, 8-HH), 1.99 (1H, 4.50 (1H, d, J = 10.4 Hz, 5-H), 5.17 (2H, s, OCH2Ph), 6.88–6.89
m, 8′-H), 2.68 (1H, ddd, J = 9.0, 5.3, 5.3 Hz, 7-H), 3.58 (1H, d, J (2H, m), 6.98 (1H, s), 7.30 (1H, m), 7.36 (2H, m), 7.43 (2H, m).
= 9.4 Hz, 7′-H), 3.83 (3H, s, OCH3), 3.90 (3H, s, OCH3), 5.49 13C NMR (100 MHz, CDCl3) δ 10.2 (4-CH3), 16.4 (2-CH3), 49.5
(1H, s, OH), 5.55 (1H, s, OH), 6.44 (1H, s), 6.64 (1H, d, J = 1.9 (4-C), 56.0 (OCH3), 71.0 (OCH2Ph), 77.8 (2-C), 84.5 (5-C), 109.9,
Hz), 6.70 (1H, dd, J = 7.9, 1.9 Hz), 6.72 (1H, s), 6.86 (1H, d, J = 113.8, 118.9, 127.2, 127.8, 128.5, 132.0, 137.0, 148.3, 149.9,
7.9 Hz). 13C NMR (100 MHz, CDCl3) δ 10.9 (9-C), 17.6 (9′-C), 217.9 (CvO). FABMS 326 (M+). Anal. found: C 73.81%, H
24.9 (8-C), 50.9 (8′-C), 51.5 (7-C), 55.9 (OCH3), 56.2 (OCH3), 6.88%; calcd for C20H22O4: C 73.60%, H 6.79%. ent-2-epi-16.
58.4 (7′-C), 105.7, 110.6, 110.7, 114.1, 121.5, 136.3, 137.7, Colorless crystals, mp 98–99 °C, [α]2D5 +58 (c 0.6, CHCl3).
139.1, 144.1, 144.5, 145.7, 146.5; EIMS m/z (%): 328 (M+, 70), Furanol 22 was obtained by the reaction of 2-epi-16 with 4-ben-
299 (100). HRMS (EI): calculated C20H24O4: 328.1675, found: zyloxy-3-methoxyphenyllithium at −70 °C in 94% yield as a
328.1666. >99%ee (AD-H, 254 nm, 5% 2-propanol/hexane, colorless oil, [α]2D5 +36 (c 0.9, CHCl3). 1H NMR (400 MHz,
1 mL min−1, tR 45.8 min).
CDCl3) δ 0.66 (3H, d, J = 7.1 Hz, 4-CH3), 1.36 (3H, d, J = 6.3 Hz,
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2-CH3), 2.30–2.37 (1H, overlapped, 4-H), 2.35 (1H, s, OH), 3.90 m), 7.01 (1H, d, J = 1.6 Hz), 7.28 (2H, m), 7.35 (4H, dd, J = 7.3,
(3H, s, OCH3), 3.91 (3H, s, OCH3), 4.35 (1H, d, J = 7.0 Hz, 5-H), 7.3 Hz), 7.43 (4H, d, J = 7.3 Hz). 13C NMR (100 MHz, CDCl3) δ
4.46 (1H, q, J = 6.3 Hz, 2-H), 5.146 (2H, s, OCH2Ph), 5.155 (2H, 15.1 (9-C), 18.9 (9′-C), 46.5 (8-C), 56.0 (OCH3 × 2), 56.5 (7′-C),
s, OCH2Ph), 6.82–6.90 (4H, m), 7.03 (1H, d, J = 1.8 Hz), 7.09 71.0 (OCH2Ph × 2), 77.3 (8′-C), 87.4 (7-C), 110.0, 112.5, 113.7,
(1H, d, J = 1.8 Hz), 7.16 (1H, m), 7.30 (1H, m), 7.33–7.38 (4H, 113.8, 118.4, 120.5, 127.16, 127.20, 127.7, 128.4, 132.5, 134.5,
m), 7.42 (2H, d, J = 6.6 Hz), 7.44 (2H, d, J = 6.8 Hz). 13C NMR 137.2, 146.8, 147.6, 149.4, 149.6. FABMS 525 (M + H)+. HRMS
(100 MHz, CDCl3) δ 14.5 (4-CH3), 15.7 (2-CH3), 54.2 (4-C), 55.97 (FAB): calculated C34H37O5: 525.2641, found: 525.2630.
(OCH3), 56.04 (OCH3), 70.9 (OCH2Ph), 71.0 (OCH2Ph), 79.6
(2-C), 84.1 (5-C), 86.5 (3-C), 110.0, 110.5, 113.2, 113.9, 118.2,
ent-7′-epi-23. Colorless oil, [α]2D5 +55 (c 0.7, CHCl3).
(2S,3S,4S,5S)-2,4-Bis(4-hydroxy-3-methoxyphenyl)-3,5-dimethyl-
118.5, 127.18, 127.23, 127.7, 127.8, 128.47, 128.50, 134.1, tetrahydrofuran, (7S,7′S,8S,8′S)-3,3′-dimethoxyl-7,8′-epoxy-8,7′-neo-
134.7, 137.0, 137.1, 147.4, 147.7, 149.4, 149.7. FABMS 541 (M + lignan-4,4′-diol 24. The phenol 24 was obtained by the hydroge-
H)+. Anal. found: C 75.75%, H 6.84%; calcd for C34H36O6: C nolysis of 23 using 5% Pd/C in EtOAc under H2 gas in 100%
75.53%, H 6.71%.
yield as a colorless oil, [α]2D5 +43 (c 0.4, CHCl3). 1H NMR
(400 MHz, CDCl3) δ 0.66 (3H, d, J = 7.0 Hz, 9-H), 1.43 (3H, d, J
ent-22. Colorless oil, [α]2D5 −37 (c 0.4, CHCl3).
(2S,3S,4S,5S)-2,4-Bis(4-benzyloxy-3-methoxyphenyl)-3,5-dimethyl- = 6.1 Hz, 9′-H), 2.36 (1H, m, 8-H), 3.02 (1H, dd, J = 8.4, 5.7 Hz,
tetrahydrofuran, (7S,7′S,8S,8′S)-4,4′-dibenzyloxy-3,3′-dimethoxyl- 7′-H), 3.88 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.44 (1H, dq, J =
7,8′-epoxy-8,7′-neolignan 23. A reaction mixture of 3-furanol 22 6.0, 6.0 Hz, 8′-H), 4.48 (1H, d, J = 8.1 Hz, 7-H), 5.59 (2H, br s,
(0.28 g, 0.52 mmol), ZnI2 (0.25 g, 0.78 mmol), and NaBH3CN OH × 2), 6.68–6.71 (2H, m), 6.84 (1H, dd, J = 8.2, 1.6 Hz),
(0.24 g, 3.82 mmol) in 1,2-dichloroethane (15 mL) was heated 6.86–6.89 (2H, m), 6.92 (1H, d, J = 1.6 Hz). 13C NMR (100 MHz,
under reflux for 4 h before adding to H2O. The mixture was CDCl3) δ 13.6 (9-C), 21.6 (9′-C), 46.1 (8-C), 55.8 (7′-C), 55.9
extracted with CH2Cl2. The organic solution was separated and (OCH3), 56.0 (OCH3), 80.0 (8′-C), 87.3 (7-C), 108.6, 111.3, 114.1,
dried (Na2SO4). Concentration followed by silica gel column 119.1, 121.5, 132.0, 134.1, 144.1, 145.0, 146.3, 146.5. EIMS m/z
chromatography (EtOAc/hexane
= 1/4) gave 23 (73 mg, (%): 344 (56), 300 (100), 285 (39). HRMS (EI): calculated
0.14 mmol, 27%) as a colorless oil, [α]2D5 +44 (c 0.3, CHCl3). C20H24O5: 344.1624, found: 344.1617. >99%ee (AD-H, 254 nm,
3-Furanol 22 (0.19 g, 0.37 mmol, 71%) was recovered. H NMR 20% 2-propanol/hexane, 1 mL min−1, tR 11.6 min).
1
(400 MHz, CDCl3) δ 0.66 (3H, d, J = 6.9 Hz, 9′-H), 1.43 (3H, d, J
ent-24. Colorless oil, [α]2D5 −45 (c 0.2, CHCl3). >99%ee
= 6.1 Hz, 9-H), 2.38 (1H, m, 8-H), 3.03 (1H, dd, J = 8.4, 5.7 Hz, (AD-H, 254 nm, 20% 2-propanol/hexane, 1 mL min−1, tR
7′-H), 3.89 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.45 (1H, dq, J = 18.0 min).
5.9, 5.9 Hz, 8′-H), 4.49 (1H, d, J = 8.7 Hz, 7-H), 5.15 (4H, s,
OCH2Ph × 2), 6.69 (1H, dd, J = 8.2, 1.8 Hz), 6.75 (1H, d, J = 1.8 tetrahydrofuran,
(2S,3S,4R,5S)-2,4-Bis(4-hydroxy-3-methoxyphenyl)-3,5-dimethyl-
(7S,7′R,8S,8′S)-3,3′-dimethoxyl-7,8′-epoxy-8,7′-
Hz), 6.84–6.86 (3H, m), 6.96 (1H, d, J = 1.1 Hz), 7.27–7.32 (2H, neolignan-4,4′-diol 7′-epi-24. The phenol 7′-epi-24 was obtained
m), 7.34–7.39 (4H, m), 7.42–7.46 (4H, m). 13C NMR (100 MHz, by the hydrogenolysis of 7′-epi-23 using 5% Pd/C in EtOAc
CDCl3) δ 13.6 (9-C), 21.6 (9′-C), 46.0 (8-C), 55.7 (7′-C), 56.0 under H2 gas in 96% yield as a colorless oil, [α]2D5 −69 (c 1.2,
1
(OCH3), 56.1 (OCH3), 71.1 (OCH2Ph × 2), 79.9 (8′-C), 87.2 (7-C), CHCl3). H NMR (400 MHz, CDCl3) δ 0.97 (3H, d, J = 6.4 Hz,
109.9, 112.8, 113.7, 113.8, 118.4, 120.7, 127.2, 127.3, 127.7, 9-H), 1.04 (3H, d, J = 6.4 Hz, 9′-H), 2.29 (1H, m, 8-H), 3.16 (1H,
127.8, 128.5, 133.2, 135.4, 137.2, 146.8, 147.5, 149.4, 149.6. dd, J = 9.7, 8.5 Hz, 7′-H), 3.87 (3H, s, OCH3), 3.93 (3H, s,
FABMS 525 (M + H)+. HRMS (FAB): calculated C34H37O5: OCH3), 4.41–4.47 (1H, overlapped, 8′-H), 4.42 (1H, d, J = 9.2
525.2641, found: 525.2632.
Hz, 7-H), 5.56 (2H, br s, OH × 2), 6.66 (1H, d, J = 1.6 Hz), 6.69
(1H, dd, J = 8.1, 1.6 Hz), 6.87 (1H, d, J = 8.1 Hz), 6.92 (2H, s),
ent-23. Colorless oil, [α]2D5 −44 (c 0.2, CHCl3).
(2S,3S,4R,5S)-2,4-Bis(4-benzyloxy-3-methoxyphenyl)-3,5-dimethyl- 6.98 (1H, s). 13C NMR (100 MHz, CDCl3) δ 15.0 (9-C), 19.0 (9′-
tetrahydrofuran,
(7S,7′R,8S,8′S)-4,4′-dibenzyloxy-3,3′-dimethoxyl- C), 46.5 (8-C), 55.9 (OCH3), 56.6 (7′-C), 76.7 (8′-C), 87.6 (7-C),
7,8′-epoxy-8,7′-neolignan 7′-epi-23. To a solution of 3-furanol 22 108.8, 111.2, 114.1, 119.3, 121.3, 131.3, 133.4, 144.3, 145.1,
(0.16 g, 0.30 mmol) and Et3SiH (2.00 mL, 12.5 mmol) in 146.4, 146.5. EIMS m/z (%): 344 (28), 300 (100), 285 (34). HRMS
CH2Cl2 (10 mL) was added BF3·OEt2 (40 μL, 0.32 mmol) at (EI): calculated C20H24O5: 344.1624, found: 344.1631. >99%ee
0 °C. The reaction solution was stirred at 0–3 °C for 30 min (AD-H, 254 nm, 20% 2-propanol/hexane, 1 mL min−1, tR
before the addition of sat. aq. NaHCO3. The organic solution 23.4 min).
was separated and dried (Na2SO4). Concentration followed by
ent-7′-epi-24. Colorless oil, [α]2D5 +69 (c 0.4, CHCl3). 97%ee
silica gel column chromatography (EtOAc/hexane = 1/3) gave (AD-H, 254 nm, 20% 2-propanol/hexane, 1 mL min−1, tR
7′-epi-23 (87 mg, 0.17 mmol, 57%) as a colorless oil, [α]2D5 −55 29.6 min).
(c 1.3, CHCl3), and 23 (4.8 mg, 0.0091 mmol, 3%). 1H NMR
(400 MHz, CDCl3) δ 0.96 (3H, d, J = 6.4 Hz, 9-H), 1.03 (3H, d, J
= 6.5 Hz, 9′-H), 2.30 (1H, m, 8-H), 3.15 (1H, dd, J = 9.3, 8.3 Hz,
7′-H), 3.84 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.40–4.46 (1H,
overlapped, 8′-H), 4.41 (1H, d, J = 9.2 Hz, 7-H), 5.12 (2H, s,
OCH2Ph), 5.15 (2H, s, OCH2Ph), 6.66 (1H, dd, J = 8.2, 1.6 Hz),
Conflicts of interest
6.70 (1H, d, J = 1.6 Hz), 6.83 (1H, d, J = 8.2 Hz), 6.86–6.92 (2H, There are no conflicts to declare.
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K. Nakayama, H. Nishiwaki and Y. Shuto, Bioorg. Med.
Chem. Lett., 2014, 24, 4798–4803.
Acknowledgements
Part of this work was performed at ADRES (Johoku station) of
Ehime University. We are grateful to Marutomo Co. for finan-
cial support.
5 T. Wukirsari, H. Nishiwaki, K. Nishi, T. Sugahra,
K. Akiyama, T. Kishida and S. Yamauchi, Biosci. Biotechnol.
Biochem., 2016, 80, 669–675.
6 G. P. Moss, Pure Appl. Chem., 2000, 72, 1493–1523.
7 (a) Y. Lu, Y. Xue, J. Liu, G. Yao, D. Li, B. Sun, J. Zhang,
Y. Liu, C. Qi, M. Xiang, Z. Luo, G. Du and Y. Zhang, J. Nat.
Prod., 2015, 78, 2205–2214; (b) O. Muraoka, T. Sawada,
E. Morimoto and G. Tanabe, Chem. Pharm. Bull., 1993, 41,
772–774; (c) T. Tsuruga, Y. Ebizuka, J. Nakajima,
Y.-T. Chun, H. Noguchi, Y. Iitaka, U. Sankawa and H. Seto,
Tetrahedron Lett., 1984, 25, 4129–4132.
8 E. Gao, Z.-Q. Zhou, J. Zou, Y. Yu, X.-L. Feng, G.-D. Chen,
R.-R. He, X.-S. Yao and H. Gao, J. Nat. Prod., 2017, 80,
2923–2929.
9 (a) B. D. Dickson, N. Dittrich and D. Barker, Tetrahedron
Lett., 2012, 53, 4464–4468; (b) B. M. Pérez, D. Schuch and
J. Hartung, Org. Biomol. Chem., 2008, 6, 3532–
3541; (c) M. Greb, J. Hartung, F. Köhler, K. Spehar,
R. Kluge and R. Csuk, Eur. J. Org. Chem., 2004, 3799–
3812.
Notes and references
1 (a) S. Fujisawa and Y. Kadoma, Mini-Rev. Med. Chem., 2012,
12, 477–490; (b) D. R. M. Arenas, A. M. Acevedo,
L. Y. V. Méndez and V. V. Kouznetsov, Sci. Pharm., 2011, 79,
779–791; (c) T. Atsumi, K. Tonosaki and S. Fujisawa, Arch.
Oral Biol., 2006, 51, 913–921; (d) T. Atsumi, Y. Murakami,
K. Shibuya, K. Tonosaki and S. Fujisawa, Anticancer Res.,
2005, 25, 4029–4036; (e) Y. Murakami, M. Shoji, A. Hirata,
S. Tanaka, I. Yokoe and S. Fujisawa, Arch. Biochem.
Biophys., 2005, 434, 326–332; (f) S. Fujisawa, T. Atsumi,
Y. Murakami and Y. Kadoma, Arch. Immunol. Ther. Exp.,
2005, 53, 28–38; (g) T. Atsumi, S. Fujisawa, K. Satoh,
H. Sakagami, I. Iwakura, T. Ueha, Y. Sugita and I. Yokoe,
Anticancer Res., 2000, 20, 2519–2524; (h) C.-H. Lin,
Y.-H. Kuo, Y.-L. Lin and C.-M. Teng, J. Pharm. Pharmacol.,
1994, 46, 54–57.
10 J. MacMillan, I. L. Martin and D. J. Morris, Tetrahedron,
1969, 25, 905–914.
11 D. A. Evans, J. S. Tedrow, J. T. Shaw and C. W. Downey,
J. Am. Chem. Soc., 2002, 124, 392–393.
12 Y. Ogura, H. Sato and S. Kuwahara, Org. Lett., 2016, 18,
2399–2402.
2 (a) T. Yamamoto, B. Riehi, K. Naba, K. Nakahara, A. Wiebe,
T. Saitoh, S. R. Waldvogel and Y. Einaga, Chem. Commun.,
2018, 54, 2771–2773; (b) N. Morita, R. Mashiko, D. Hakuta,
D. Eguchi, S. Ban, Y. Hashimoto, I. Okamoto and
O. Tamura, Synthesis, 2016, 1927–1933.
13 F. A. Carey and H. S. Tremper, J. Org. Chem., 1969, 34,
4–6.
3 T. Nakato, S. Yamauchi, R. Tago, K. Akiyama,
M. Maruyama, T. Sugahara, T. Kishida and Y. Koba, Biosci.
Biotechnol. Biochem., 2009, 73, 1608–1617.
14 C.
K.
Lau,
C.
Dufresne,
P.
C.
Belanger,
S. Pietre and J. Scheigetz, J. Org. Chem., 1986, 51, 3038–
3043.
4 (a) H. Nishiwaki, K. Nakayama, Y. Shuto and S. Yamauchi,
J. Agric. Food Chem., 2014, 62, 651–659; (b) S. Yamauchi,
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