Determination of the stereochemistry of the tetrahydropyran sesquineolignans morinols A and B

Article abstract of DOI:10.1021/np060461j

The 7′,8′-stereochemistry of the tetrahydropyran sesquineolignans morinols A and B was determined as threo via synthetic studies and by comparison of NMR data of 7′,8′-threo-morinol and 7′,8′-erythro-morinol. This study also confirmed that the biosynthetic process produces enantiomeric mixtures of morinols A and B. This was ascertained by comparing the specific rotations of synthesized morinols A and B with those of naturally occurring morinols A and B.

Full text of DOI:10.1021/np060461j

J. Nat. Prod. 2007, 70, 549-556
549
Determination of the Stereochemistry of the Tetrahydropyran Sesquineolignans
Morinols A and B
Satoshi Yamauchi,*,† Takuya Sugahara,† Koichi Akiyama,‡ Masafumi Maruyama,† and Taro Kishida†
Faculty of Agriculture, Ehime UniVersity, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan, and Integrated Center for Sciences, Tarumi
Station, Ehime UniVersity, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566 Japan
ReceiVed September 18, 2006
The 7′,8′-stereochemistry of the tetrahydropyran sesquineolignans morinols A and B was determined as threo via synthetic
studies and by comparison of NMR data of 7′,8′-threo-morinol and 7′,8′-erythro-morinol. This study also confirmed
that the biosynthetic process produces enantiomeric mixtures of morinols A and B. This was ascertained by comparing
the specific rotations of synthesized morinols A and B with those of naturally occurring morinols A and B.
The unique tetrahydropyran sesquineolignans morinols A and
B have been isolated from the Chinese traditional medicinal plant
Morina chinensis as a racemic mixture (Figure 1).1,2 The inhibition
of cytokines by morinols A and B and the stronger activity of
morinol B than morinol A have also been reported.2 This activity
of lignans on cytokines is rare, even though many biological
activities of naturally occurring lignans are known.3,4 The biosyn-
thesis of enantiomeric lignans has also been reported.5 Therefore,
the synthesis of optically pure lignans is important to determine
their precise biological activity. The relationship between lignan
structure and biological activity is complex because of numerous
combinations of phenylpropanoid units and oxidation patterns. The
synthesis and characterization of lignans6 are continuing to clarify
which structural features of lignans determine biological activity.
Morinols A and B were obtained as a racemic mixture from natural
sources and used for biological research. The relative configuration
of the 7′ and 8′ stereocenters are undefined. These facts persuaded
us to synthesize optically pure morinols A and B to define their
absolute configuration. The success of the synthetic study of
morinols A and B would also contribute to research about the
structure/activity relationship of tetrahydropyran sesquineolignans.
Furthermore, the precise biological activity could be determined
and new factors responsible for the biological activity of the novel
structure would be clarified. A chiral secondary benzyl alcohol
adjacent to another chiral carbon is common in lignan structures.4
These functionalities occur in both erythro and threo forms.
However, the determination of the relative configuration is prob-
lematic. Thus syntheses of 7′,8′-threo-morinols A and B and 7′,8′-
erythro-morinols A and B were performed to determine their
stereochemistries.
Figure 1. Morinol A and morinol B were isolated as enantiomeric
mixtures.1,2
Results and Discussion
The synthetic plan is shown in Figure 2. The tetrahydropyran
ring was obtained by SN2 etherification between the benzyl alcohol
and primary mesylate. The C-7 chiral carbon was constructed by a
Grignard reaction. The C-8 chiral carbon was asymmetrically
introduced by allylation using Evans’ chiral auxiliary. The selection
of morinol A (8,8′-cis) type or morinol B (8,8′-trans) type was
achieved by S or R Evans’ auxiliary before this allylation. The
stereocontrol of erythro or threo between C-7′ and C-8′ was
achieved by an Evans’ syn7 or anti8 selective aldol condensation,
respectively. This synthetic strategy could be readily applied to
morinol A and B derivatives. Thus, the introduction of a 3′′,4′′-
dimethoxyphenyl group at C-7′′ using a Pd catalyst was planned.
Figure 2. Synthetic plan of morinols A and B.
This article shows the determination of the stereochemistry of
both morinols A and B by their first in Vitro synthesis. A new
example of lignan biosynthesis as an enantiomeric mixture is also
confirmed by comparison of the specific rotations of synthesized
morinols A and B with those of previously isolated morinols A
and B.1,2
The plan for the construction of the tetrahydropyran structure
17, which has the 7′,8′-threo-morinol B configuration, required the
synthesis of substrate 15 (Scheme 1). The chiral carbons of 15 were
introduced by Evans’ anti-aldol8 condensation, allylation by
employing Evans’ chiral auxiliary, and a Grignard reaction. The
Evans’ anti-aldol condensation between 3 and 3,4-dimethoxyben-
zaldehyde employing Et3N, chlorotrimethylsilane, and MgCl2 gave
4 (93% yield), which was transformed to silyl ether 5 by using
* To whom correspondence should be addressed. Tel: +81-89-946-9846.
Fax: +81-89-977-4364. E-mail: syamauch@agr.ehime-u.ac.jp.
† Faculty of Agriculture, Ehime University.
‡ Integrated Center for Science, Tarumi Station, Ehime University.
10.1021/np060461j CCC: $37.00
© 2007 American Chemical Society and American Society of Pharmacognosy
Published on Web 02/16/2007

550 Journal of Natural Products, 2007, Vol. 70, No. 4
Scheme 1. Synthesis of Morinol Ba
Yamauchi et al.
a
(a) 5-hexenoic acid, Et3N, PivCl, THF, 0 °C, 1 h, then lithium salt of (S)-4-benzyl-2-oxazolidinone, THF, from -70 to 0 °C, 1 h (80% yield); (b) (1) Et3N,
TMSCl, MgCl2, 3,4-dimethoxybenzaldehyde, EtOAc, rt, 16 h; (2) TFA, MeOH, rt, 30 min (93% yield); (c) TIPSOTf, 2,6-lutidine, CH2Cl2, rt, 1 h (91% yield); (d)
LiBH4, MeOH, THF, rt, 6 h (60% yield); (e) TrCl, DMAP, C5H5N, 60 °C, 16 h (81% yield); (f) (1) OsO4, NMO, aq acetone, tert-BuOH, rt, 16 h; (2) NaIO4, MeOH,
rt, 3 h; (3) 2-methyl-2-butene, NaH2PO4‚2H2O, NaClO2, aq tert-BuOH, rt, 1 h (86% yield); (g) Et3N, PivCl, 0 °C, 1 h, then lithium salt of (S)-4-benzyl-2-oxazolidinone,
from -70 to 0 °C, 1 h (88% yield); (h) KHMDS, allyl bromide, THF, from -70 °C to rt, 16 h (50% yield); (i) LiBH4, MeOH, THF, rt, 1 h (89% yield); (j) PCC, MS
4Å, CH2Cl2, rt, 16 h (76% yield); (k) 3,4-(MeO)2PhMgBr, THF, rt, 1 h (93% yield); (l) (1) Ac2O, C5H5N, rt, 16 h; (2) HCO2H, ether, -5 °C, 10 min (14: 35% yield,
15: 38% yield); (m) (1) MsCl, Et3N, CH2Cl2, 0 °C, 30 min; (2) K2CO3, MeOH, rt, 16 h; (3) NaH, DMF, rt, 16 h (70% yield); (n) (1) MsCl, Et3N, CH2Cl2, 0 °C, 30
min; (2) K2CO3, MeOH, rt, 16 h (56% yield); (o) 1-Br-3,4-(MeO)2C6H3, Et3N, PdCl2(PPh3)2, DMF, 90 °C, 6 h (33% yield, recovered 17, 58%); (p) n-Bu4NF, THF,
rt, 3 h (100% yield).
triisopropylsilyl triflate and 2,6-lutidine. The trityl ether 7 was
obtained by reductive (LiBH4) removal of the chiral auxiliary of 5
(60% yield) followed by treatment with trityl chloride in pyridine
(81% yield). To introduce the Evans’ chiral auxiliary, olefin 7 was
converted to carboxylic acid 8 by OsO4 oxidation, then NaIO4
oxidation and then NaClO2 oxidation (86% yield, three steps).
Attachment of S-Evans’ chiral auxiliary to carboxylic acid 8 was
achieved by coupling of the pivaloic anhydride of carboxylic acid
8 with the lithium salt of (S)-4-benzyl-2-oxazolidinone in 88% yield.
The stereoselective allylation to 9 was accomplished by employing
potassium bis(trimethylsilylamide) and allyl bromide to give 10
(50% yield) as a single isomer. Formation of the other stereoisomer
was not observed. Since the R-allylation to the lactone, which was
obtained from 8 by detritylation, gave the diallyl compound,
allylation using a chiral auxiliary was adopted. The allylation using
sodium bis(trimethylsilylamide) did not give the allyl product.
Reductive (LiBH4) removal of the chiral auxiliary of 10 (89% yield)
followed by pyridinium chlorochromate oxidation (76% yield) gave
aldehyde 12. Treatment of aldehyde 12 with 3,4-dimethoxyphe-
nylmagnesium bromide gave benzyl alcohol 13 as a 1:1 mixture
of diastereomers in 93% yield. Detritylation of 13 using formic
acid in ether was accompanied by desilylation, giving the corre-
sponding triol. However, detritylation of acetate of 13 gave
separable alcohols 14 (35% yield) and 15 (38% yield). At this stage,
the cyclization of the substrate to tetrahydropyran was obtained.
The configurations of 14 and 15 were not determined at this stage.
After conversion of 15 to the corresponding mesylate by using
MeSO2Cl and Et3N, the resulting crude mesylate was exposed to
K2CO3 in MeOH, giving tetrahydropyran 17 in 56% yield.
The Mizorogi-Heck reaction is known to couple an aryl halide
with a conjugate olefin or enol using Pd catalysis. However, olefin
17 is not a conjugate olefin. This case is not typical of coupling
reactions using Pd catalysts. Cesati et al. have reported Pd catalytic
coupling reactions between aryl bromide and ethylene using PdCl2-
(PPh3)2.9 The PdCl2(PPh3)2-catalyzed coupling reaction between
1-bromo-3,4-dimethoxybenzene and olefin 17 was carried out in
DMF at 90 °C, giving trans-olefin 18 in 33% yield. A 58% portion
of olefin 17 was recovered. Only the trans-olefin showing a
coupling constant of 16.1 Hz for H-7′′ and H-8′′ was obtained.
The formation of cis-olefin was not observed. The coupling constant
of H-7 of 18 (9.3 Hz, diaxial) became clear at this stage, showing
the trans-configuration of the C-7-C-8 bond. To compare the
coupling constant of H-7, the 7,8-cis-compound 16 was prepared
from Grignard product 14 by mesylation and deacetylation followed
by treatment with sodium hydride in DMF. The H-7 coupling
constant of the 7,8-cis-compound 16 was 2.0 Hz (axial-equatorial).
Finally, desilylation of 18 by treatment with TBAF gave (+)-
morinol B in quantitative yield. NMR data agreed with those in
the literature.1,2 (-)-Morinol B was also synthesized from (R)-3
by almost the same synthetic method. In the step for introduction
of a chiral auxiliary before allylation, (R)-Evans’ chiral auxiliary
was employed. These facts mean that the relative configuration of
the C-7′-C-8′ bond of naturally occurring morinol B is threo. The
specific rotations of synthesized (+)- and (-)-morinol B were +69
and -69, respectively. On the other hand, specific rotation of
isolated morinol B was reported as -3.92.1,2 This shows that
morinol B was biosynthesized as an enantiomeric mixture. The
enantiomeric excess of synthesized (+)- and (-)-morinol B was
established as more than 99% each by HPLC analysis using a chiral
column.
The next key step involved formation of the cinnamyl compound
by the coupling of aryl halide with olefin employing a Pd catalyst.

Stereochemistry of Tetrahydropyran Sesquineolignans
Journal of Natural Products, 2007, Vol. 70, No. 4 551
Scheme 2. Synthesis of Morinol Aa
a
(a) Et3N, PivCl, 0 °C 1 h, then lithium salt of (R)-4-benzyl-2-oxazolidinone, from -70 to 0 °C, 1 h (83% yield); (b) KHMDS, allyl bromide, THF, from -70 °C
to rt, 16 h (59% yield); (c) LiBH4, MeOH, THF, rt, 1 h (90% yield); (d) PCC, MS 4Å, CH2Cl2, rt, 16 h (100% yield); (e) 3,4-(MeO)2PhMgBr, THF, rt, 1 h (23: 28%
yield, 24: 26% yield); (f) (1) Ac2O, C5H5N, rt, 16 h; (2) HCO2H, ether, -5 °C, 10 min (25: 58% yield, 26: 59% yield); (g) (1) MsCl, Et3N, Ch2Cl2, 0 °C, 30 min;
(2) K2CO3, MeOH, rt, 16 h; (3) NaH, DMF, rt, 16 h (95% yield); (h) (1) MsCl, Et3N, CH2Cl2, 0 °C, 30 min; (2) K2CO3, MeOH, rt, 16 h (54% yield); (i) n-Bu4NF,
THF, rt, 3 h (94% yield); (j) 1-Br-3,4-(MeO)2C6H3, Et3N, PdCl2(PPh3)2, DMF, 90 °C, 6 h (31% yield, recovered 29, 67%).
To synthesize 7′,8′-threo-morinol A, carboxylic acid 8 was
selected as a starting material (Scheme 2). After attachment of
R-Evans’ chiral auxiliary, the resulting compound 19 was converted
to Grignard products 23 and 24. Compound 24 was transformed to
allyl tetrahydropyran 29 to examine the olefin coupling reaction
using an olefin without a silyl group. The coupling reaction of olefin
29 with 1-bromo-3,4-dimethoxybenzene using PdCl2(PPh3)2 gave
(-)-morinol A (31% yield) and recovered olefin 29 (67%). NMR
data agreed with those in the literature.1,2 (+)-Morinol A was also
synthesized by the same method. It was confirmed that the relative
configuration of the C-7′-C-8′ bond of naturally occurring morinol
A is also the threo form and morinol A is biosynthesized as an
enantiomeric mixture. The specific rotations of synthesized (+)-
and (-)-morinol A were +15 and -15, respectively. On the other
hand, the specific rotation of isolated morinol B was reported as
+0.98.1,2 The HPLC analysis using a chiral column showed that
the enantiomeric excess of synthesized (+)- and (-)-morinol A
was more than 99% ee.
To ensure the stereochemistry of morinols A and B, (-)-7′,8′-
erythro-morinols A (31) and B (32) were synthesized from Evans’
syn aldol product 30 (Scheme 3). The 13C NMR spectrum of (+)-
7′,8′-erythro-morinol B (32) was different from that of (+)-7′,8′-
threo-morinol B (2); however, the 13C NMR spectrum of (-)-7′,8′-
erythro-morinol A (31) was similar to that of (-)-7′,8′-threo-
morinol A (1). A clear difference between the 7′,8′-threo and 7′,8′-
erythro isomers was observed in the chemical shifts of H2-9, H-7′′,
and H-8′′. The H2-9′ of the 7′,8′-threo isomers (morinol A: 3.42
and 4.38 ppm; morinol B: 3.74 and 4.50 ppm) resonates at lower
field than that of the 7′,8′-erythro isomers (morinol A: 3.28 and
3.84-3.89 ppm, morinol B: 3.64 and 3.86-3.92 ppm). Both H-7′′
and H-8′′ of the 7′,8′-threo isomers (morinol A: H-7′′, 6.09 ppm,
H-8′′, 5.71 ppm; morinol B: H-7′′, 6.08 ppm, H-8′′, 5.69 ppm)
resonate at higher field than those of the 7′,8′-erythro isomers
(morinol A: H-7′′, 6.17 ppm, H-8′′, 5.85 ppm; morinol B: H-7′′,
6.19 ppm, H-8′′, 5.87 ppm). The coupling constants of H-7′ of the
7′,8′-threo isomers (morinol A: 9.1 Hz; morinol B: 9.0 Hz) were
larger than those of the 7′,8′-erythro isomers (morinol A: 7.3 Hz;
morinol B: 8.5 Hz).
The stereochemistry of naturally occurring tetrahydropyran
sesquineolignans morinols A and B was determined as 7′,8′-threo
by enantioselective syntheses of (+)- and (-)-morinols A and B.
The syntheses of the 7′,8′-erythro isomer permitted the comparison
of chemical shifts. This research will contribute to biosynthetic and
biological research on neolignans.
Experimental Section
General Experimental Procedures. Melting points were not
corrected. Optical rotations were measured on a Horiba SEPA-200
instrument. NMR data were obtained using a JNM-EX400 spectrometer.
EIMS data were measured with a JMS-MS700V spectrometer. The
silica gel used was Wakogel C-300 (Wako, 200-300 mesh). HPLC
analysis was performed with Shimadzu LC-6AD and SPD-6AV
instruments. The numbering of compounds follows IUPAC nomencla-
tural rules.
(S)-4-Benzyl-3-(5-hexenoyl)-2-oxazolidinone (3). To a solution of
5-hexenoic acid (8.43 mL, 0.071 mol) in THF (200 mL) were added
Et3N (9.90 mL, 0.071 mol) and pivaloyl chloride (8.74 mL, 0.071 mol)
at -70 °C, and then the mixture was stirred at 0 °C for 1 h. After
cooling to -70 °C, a solution of the lithium salt of (S)-4-benzyl-2-
oxazolidinone prepared from (S)-4-benzyl-2-oxazolidinone (12.5 g,
0.071 mol) and n-BuLi (1.6 M in THF, 44.4 mL, 0.071 mol) at -70
°C in THF (150 mL) was added, and then the reaction mixture was
stirred at 0 °C for 1 h. After addition of a saturated aqueous NH4Cl
solution, the solution was separated, washed with brine, and dried (Na2-
SO4). Concentration followed by silica gel column chromatography
(EtOAc/hexane, 1:3) gave acyloxazolidinone 3 (15.6 g, 0.057 mol, 80%)
1
as a colorless oil: [R]20 +69 (c 0.3, CHCl3); H NMR (CDCl3) δ
D

552 Journal of Natural Products, 2007, Vol. 70, No. 4
Yamauchi et al.
Scheme 3. Syntheses of (-)-7′,8′-erythro-Morinol A and (+)-7′,8′-erythro-Morinol Ba
a
(a) 3,4-(MeO)2C6H3CHO, Bu2BOTf, Et3N, CH2Cl2, from -65 to 0 °C, 1 h (100% yield).
1.77-1.85 (2H, m, H2-3 of hexenoyl), 2.13-2.19 (2H, m, H2-2 of
hexenoyl), 2.77 (1H, dd, J ) 13.5, 9.5 Hz, CH2aPh), 2.87-3.03 (2H,
m, H2-4 of hexenoyl), 3.29 (1H, dd, J ) 13.5, 3.4 Hz, CH2bPH), 4.14-
4.22 (2H, m, H2-5), 4.67 (1H, m, H-4), 4.99-5.08 (2H, m, H2-6 of
hexenoyl), 5.82 (1H, m, H-5), 7.20-7.21 (2H, m, ArH), 7.26-7.29
(1H, m, ArH), 7.30-7.35 (2H, m, ArH); 13C NMR (CDCl3) δ 23.3,
33.0, 34.8, 37.9, 55.1, 66.1, 115.3, 127.3, 128.9, 129.4, 135.3, 137.8,
153.4, 173.1; anal. C 70.50%, H 7.02%, N 5.10%, calcd for C16H19O3N,
1.76 (1H, m, H-2), 2.00 (1H, m, H-4a), 2.13 (1H, m, H-4b), 2.78 (1H,
dd, J ) 5.9, 4.9 Hz, OH), 3.57 (1H, ddd, J ) 11.2, 5.9, 5.9 Hz, H-1a),
3.82 (1H, m, H-1b), 3.88 (6H, s, OCH3), 4.85 (1H, d, J ) 5.4 Hz,
ArCHOSi), 4.91-4.99 (2H, m, H2-6), 5.72 (1H, m, H-5), 6.75-6.83
(2H, m, ArH), 6.93 (1H, s, ArH); 13C NMR (CDCl3) δ 12.5, 18.0, 18.1,
27.0, 31.5, 47.8, 55.8, 63.0, 79.2, 109.9, 110.4, 114.7, 119.1, 136.1,
138.5, 148.3, 148.7; anal. C 67.75%, H 10.30%, calcd for C24H42O4Si,
C 68.20%, H 10.02%. (R)-[(R)]-6: [R]20 +48 (c 0.4, CHCl3).
D
C 70.31%, H 7.01%, N 5.12%. (R)-3: [R]20 -69 (c 1.9, CHCl3).
(5S,6S)-6-(3,4-Dimethoxyphenyl)-6-(triisopropylsilyloxy)-5-trity-
loxymethyl-1-hexene (7). A mixture of alcohol 6 (15.2 g, 0.036 mol)
and trityl chloride (10.0 g, 0.036 mol), and DMAP (0.1 g, 0.00082
mol) in pyridine (50 mL) was stirred at 60 °C for 16 h. After addition
of H2O and EtOAc, the organic solution was separated, washed with a
saturated aqueous CuSO4 solution, a saturated aqueous NaHCO3
solution, and brine, and dried (Na2SO4). Concentration followed by
silica gel column chromatography (EtOAc/hexane, 1:9) gave trityl ether
D
(S)-4-Benzyl-3-{(R)-2-[(S)-(hydroxy)(3,4-dimethoxyphenyl)methyl]-
5-hexenoyl}-2-oxazolidinone (4). The reaction has previously been
1
described.10 Yield 93%, colorless oil: [R]20 -10 (c 2.2, CHCl3); H
D
NMR (CDCl3) δ 1.52 (1H, m, H-3a of hexenoyl), 1.89 (1H, m, H-3b
of hexenoyl), 2.02-2.07 (2H, m, H2-4 of hexenoyl), 2.57 (1H, dd, J )
13.7, 9.8 Hz, CH2aPh), 3.12 (1H, d, J ) 8.3 Hz, OH), 3.16 (1H, d, J
) 13.7, 3.4 Hz, CH2bPh), 3.86 (3H, s, OCH3), 3.90 (3H, s, OCH3),
4.09-4.16 (2H, m, H2-5), 4.48 (1H, m, 2-H of hexenoyl), 4.66 (1H,
m, H-4), 4.78 (1H, dd, J ) 8.3, 7.8 Hz, ArCHOH), 4.91-4.98 (2H, m,
H2-6 of hexenoyl), 5.71 (1H, m, H-5 of hexenoyl), 6.84 (1H, d, J )
8.3 Hz, ArH), 6.95 (1H, dd, J ) 8.3, 2.0 Hz, ArH), 7.00 (1H, d, J )
7 (19.0 g, 0.029 mol, 81%) as colorless crystals, mp 113-114 °C (i-
1
Pr2O): [R]20 -47 (c 1.2, CHCl3); H NMR (CDCl3) δ 0.69 (1H, m,
D
H-4a), 1.00-1.06 (21H, m, i-Pr), 1.70 (1H, m, H-4b), 1.81-2.04 (2H,
m, H2-3), 2.30 (1H, m, H-5), 2.66 (1H, dd, J ) 9.5, 9.5 Hz, TrOCH2a),
3.21 (1H, dd, J ) 9.5, 5.1 Hz, TrOCH2b), 3.71 (3H, s, OCH3), 3.81
(3H, s, OCH3), 4.88-4.92 (2H, m, H2-1), 5.30 (1H, d, J ) 3.9 Hz,
ArCHOSi), 5.70 (1H, m, H-2), 6.53 (2H, s, ArH), 6.85 (1H, s, ArH),
7.21-7.30 (9H, m, ArH), 7.40-7.47 (6H, m, ArH); 13C NMR (CDCl3)
δ 12.4, 18.06, 18.13, 24.4, 31.8, 46.4, 55.7, 63.8, 73.8, 86.7, 109.8,
110.4, 114.4, 119.3, 126.9, 127.7, 128.7, 134.5, 139.0, 144.3, 147.6,
148.0; anal. C 77.49%, H 8.85%, calcd for C43H56O4Si, C 77.67%, H
2.0 Hz, ArH), 7.13-7.15 (2H, m, ArH), 7.25-7.32 (3H, m, ArH); 13
C
NMR (CDCl3) δ 28.9, 31.5, 37.5, 48.6, 55.5, 55.8, 55.9, 65.8, 76.2,
109.3, 110.9, 115.2, 118.7, 127.3, 128.9, 129.4, 134.9, 135.2, 137.7,
148.7, 149.1, 153.7, 176.1; anal. C 68.13%, H 6.54%, N 2.99%, calcd
for C25H29O6N, C 68.32%, H 6.65%, N 3.19%. (R)-3-{(S)-2-[(R)]}-4:
[R]20 +10 (c 1.1, CHCl3).
D
(S)-4-Benzyl-3-{(R)-2-[(S)-(3,4-dimethoxyphenyl)(triisopropyls-
ilyloxy)methyl]-5-hexenoyl}-2-oxazolidinone (5). The reaction has
8.49%. (5R,6R)-7: [R]20 +47 (c 1.1, CHCl3).
D
previously been described.10 Yield 91%, colorless oil: [R]20 -45 (c
(4S,5S)-5-(3,4-Dimethoxyphenyl)-5-(triisopropylsilyloxy)-4-(tri-
tyloxymethyl)pentanoic Acid (8). A solution of olefin 7 (19.0 g, 0.029
mol) and 4-methylmorpholine N-oxide (3.95 g, 0.034 mol) in acetone
(250 mL), t-BuOH (50 mL), and H2O (25 mL) was stirred at room
temperature for 16 h under N2 gas. After addition of a saturated aqueous
Na2S2O3 solution, the mixture was concentrated. The residue was
dissolved in H2O and EtOAc. The organic solution was separated,
washed with brine, and dried (Na2SO4). Concentration gave a crude
glycol. A mixture of the crude glycol and NaIO4 (7.22 g, 0.034 mol)
in MeOH (150 mL) was stirred at room temperature for 3 h. After
concentration, the residue was dissolved in H2O and EtOAc. The organic
solution was separated, washed with brine, and dried (Na2SO4).
Concentration gave a crude aldehyde. To a solution of the crude
aldehyde, 2-methyl-2-butene (13.1 mL, 0.12 mol), and NaH2PO4‚2H2O
(4.37 g, 0.028 mol) in t-BuOH (200 mL) and H2O (50 mL) was added
NaClO2 (80%, 11.0 g, 0.097 mol). The solution was stirred at room
temperature for 1 h, and then CHCl3 was added. After acidification
with 1 M aqueous HCl solution, the organic solution was separated,
washed with brine, and dried (Na2SO4). Concentration followed by silica
D
3.0, CHCl3); 1H NMR (CDCl3) δ 0.86-1.00 (21H, m, i-Pr), 1.24 (1H,
m, H-3a of hexenoyl), 1.66 (1H, m, H-3b of hexenoyl), 1.86-1.90
(2H, m, H2-4 of hexenoyl), 2.62 (1H, dd, J ) 12.7, 11.2, CH2aPh),
3.58 (1H, dd, J ) 12.7, 3.2 Hz, C2bPh-4), 3.88 (3H, s, OCH3), 3.91
(3H, s, OCH3), 4.08-4.16 (2H, m, H2-5), 4.44 (1H, m, H-2 of
hexenoyl), 4.64 (1H, m, H-4), 4.84-4.89 (2H, m, H2-6 of hexenoyl),
4.98 (1H, d, J ) 8.8 Hz, ArCHOSi), 5.61 (1H, m, H-5 of hexenoyl),
6.78 (1H, d, J ) 7.8 Hz, ArH), 6.87 (1H, dd, J ) 7.8, 1.6 Hz, ArH),
7.10 (1H, d, J ) 1.6 Hz, ArH), 7.22-7.31 (3H, m, ArH), 7.34-7.38
(2H, m, ArH); 13C NMR (CDCl3) δ 12.7, 17.9, 18.1, 28.6, 31.4, 38.4,
51.0, 55.79, 55.80, 56.2, 65.9, 77.8, 110.1, 110.5, 114.8, 120.2, 127.2,
129.0, 129.3, 135.2, 136.0, 138.0, 148.8, 148.9, 153.3, 175.3; anal. C
68.44%, H 8.58%, N 2.16%, calcd for C34H49O6NSi, C 68.54%, H
8.29%, N 2.35%. (R)-{(S)-[(R)]}-5: [R]20 +45 (c 3.6, CHCl3).
D
(S)-2-[(S)-(3,4-Dimethoxyphenyl)(triisopropylsilyloxy)methyl]-5-
hexen-1-ol (6). The reaction has previously been described.10 Yield
1
60%, colorless oil: [R]20 -48 (c 1.2, CHCl3); H NMR (CDCl3) δ
D
0.97-1.03 (21H, m, i-Pr), 1.40 (1H, m, H-3a), 1.47 (1H, m, H-3b),

Stereochemistry of Tetrahydropyran Sesquineolignans
Journal of Natural Products, 2007, Vol. 70, No. 4 553
gel column chromatography (EtOAc/hexane, 1:2) gave carboxylic acid
8 (16.8 g, 0.025 mol, 86%) as a colorless oil: [R]20D -37 (c 0.3, CHCl3);
1H NMR (CDCl3) δ 0.97-1.10 (22H, m, i-Pr, H-3a), 1.86 (1H, m,
H-3b), 2.20-2.34 (3H, m, H2-2, H-4), 2.81 (1H, dd, J ) 9.3, 9.3 Hz,
H-5a), 3.12 (1H, dd, J ) 9.3, 5.6 Hz, H-5b), 3.71 (3H, s, OCH3), 3.81
(3H, s, OCH3), 5.23 (1H, d, J ) 4.4 Hz, ArCHOSi), 6.56 (2H, s, ArH),
6.83 (1H, s, ArH), 7.20-7.30 (9H, m, ArH), 7.42-7.44 (6H, m, ArH);
13C NMR (CDCl3) δ 12.3, 18.0, 18.1, 21.3, 32.4, 46.6, 55.7, 64.0, 74.2,
86.9, 110.0, 110.2, 119.3, 127.0, 127.7, 128.7, 134.1, 144.1, 147.8,
148.2, 179.6; anal. C, 73.46%, H 8.08%, calcd for C42H54O6Si, C
pentenoyl), 6.56 (2H, s, ArH), 6.88 (1H, s, ArH), 7.18-7.36 (14H, m,
ArH), 7.40-7.44 (6H, m, ArH); 13C NMR (CDCl3) δ 12.4, 18.0, 18.1,
28.5, 38.0, 38.2, 39.9, 45.2, 55.5, 55.7, 64.3, 65.7, 74.2, 86.9, 110.0,
110.4, 117.1, 119.3, 126.9, 127.2, 127.7, 128.7, 128.9, 129.3, 134.4,
134.9, 135.7, 144.1, 147.6, 148.1, 152.7, 175.5; anal. C 75.12%, H
7.68%, N 1.65%, calcd for C55H67O7NSi, C 74.88%, H 7.66%, N 1.59%.
(R)-3-{(R)-[(2R,3R)]}-10: [R]20 +25 (c 0.3, CHCl3).
D
(R)-4-Benzyl-3-{(R)-2-[(2S,3S)-3-(3,4-dimethoxypheyl)-3-(triiso-
propylsilyloxy)-2-(trityloxymethyl)prop-1-yl]-4-pentenoyl}-2-oxazo-
lidinone (20). Yield 59%, colorless oil: [R]20 -34 (c 2.7, CHCl3);
D
73.86%, H 7.97%. (4R,5R)-8: [R]20 +37 (c 1.2, CHCl3).
1H NMR (CDCl3) δ 0.88-1.15 (22H, m, i-Pr, CH-2a of pentenoyl),
1.80 (1H, m, CH-2b of pentenoyl), 2.24 (1H, m, H-3a of pentenoyl),
2.31 (1H, m, TrOCH2CH), 2.38 (1H, m, H-3b of pentenoyl), 2.55 (1H,
dd, J ) 13.3, 10.1 Hz, PhCH2a), 2.66 (1H, dd, J ) 10.0, 10.0 Hz,
TrOCH2a), 3.20 (1H, dd, J ) 13.3, 3.1 Hz, PhCH2b), 3.25 (1H, dd, J )
10.0, 4.9 Hz, TrOCH2b), 3.70 (3H, s, OCH3), 3.76 (1H, m, H-2 of
pentenoyl), 3.80 (3H, s, OCH3), 3.80-3.86 (1H, overlapped, H-5a),
4.01 (1H, dd, J ) 8.9, 2.4 Hz, H-5b), 4.41 (1H, m, H-4), 4.99-5.04
(2H, m, H2-5 of pentenoyl), 5.39 (1H, d, J ) 3.8 Hz, ArCHOSi), 5.75
(1H, m, H-4 of pentenoyl), 6.53-6.58 (2H, m, ArH), 6.87 (1H, s, ArH),
7.16-7.18 (2H, m, ArH), 7.20-7.33 (7H, m, ArH), 7.42-7.45 (6H,
m, ArH); 13C NMR (CDCl3) δ 12.3, 18.0, 18.1, 26.8, 36.9, 38.0, 41.0,
45.7, 55.5, 55.6, 55.7, 64.3, 65.6, 73.5, 87.0, 110.0, 110.4, 117.1, 119.3,
126.9, 127.2, 127.7, 128.6, 128.9, 129.3, 133.9, 135.2, 135.5, 144.1,
147.6, 148.0, 152.6, 175.8; anal. C 75.01%, H 7.70%, N 1.59%, calcd
for C55H67O7NSi, C 74.88%, H 7.66%, N 1.59%. (S)-3-{(S)-2-[(2R,3R)]-
D
(S)-4-Benzyl-3-[(4S,5S)-5-(3,4-dimethoxyphenyl)-5-(triisopropyl-
silyloxy)-4-(trityloxymethyl)pentanoyl]-2-oxazolidinone (9). To a
solution of carboxylic acid 8 (16.8 g, 0.025 mol) in THF (100 mL)
was added Et3N (3.44 mL, 0.025 mol) and PivCl (3.08 mL, 0.025 mol)
at -70 °C, and then the mixture was stirred at 0 °C for 1 h. After
cooling to -70 °C, a solution of the lithium salt of (S)-4-benzyl-2-
oxazolidinone in THF (60 mL), prepared from (S)-4-benzyl-2-oxazo-
lidinone (4.33 g, 0.024 mol) and n-BuLi (2.6 M in THF, 9.65 mL,
0.025 mol), at -70 °C in THF was added, and then the reaction mixture
was stirred at 0 °C for 1 h. After addition of a saturated aqueous NH4-
Cl solution, the solution was separated, washed with brine, and dried
(Na2SO4). Concentration followed by silica gel column chromatography
(EtOAc/hexane, 1:3) gave acyloxazolidinone 9 (18.6 g, 0.022 mol, 88%)
1
as a colorless oil: [R]20 -10 (c 0.3, CHCl3); H NMR (CDCl3) δ
D
0.97-1.08 (21H, m, i-Pr), 1.14 (1H, m, H-3a of pentanoyl), 1.89 (1H,
m, H-3b of pentanoyl), 2.30 (1H, m, H-4 of pentanoyl), 2.58 (1H, dd,
J ) 13.4, 10.0 Hz, CH2aPh-4), 2.81-2.98 (3H, m, H2-2 of pentanoyl,
TrOCH2a), 3.16 (1H, dd, J ) 9.8, 5.4 Hz, TrOCH2b), 3.22 (1H, dd, J
) 13.4, 3.2 Hz, CH2bPh), 3.74 (3H, s, OCH3), 3.82 (3H, s, OCH3),
4.08-4.10 (2H, m, H2-5), 4.57 (1H, m, H-4), 5.20 (1H, d, J ) 4.4 Hz,
ArCHOSi), 6.59 (2H, s, ArH), 6.88 (1H, s, ArH), 7.15-7.17 (2H, m,
ArH), 7.20-7.30 (12H, m, ArH), 7.43-7.45 (6H, m, ArH); 13C NMR
(CDCl3) δ 12.4, 18.0, 18.1, 20.9, 34.1, 37.8, 46.9, 55.1, 55.69, 55.73,
64.3, 66.0, 74.5, 86.9, 110.0, 110.3, 119.3, 126.9, 127.2, 127.7, 128.7,
128.9, 129.3, 134.4, 135.4, 144.1, 147.7, 148.2, 153.2, 173.2; anal. C
74.14%, H 7.63%, N 1.54%, calcd for C52H63O7NSi, C 74.16%, H
20: [R]20 +33 (c 0.5, CHCl3).
D
(S)-2-[(2S,3S)-3-(3,4-Dimethoxyphenyl)-3-(triisopropylsilyloxy)-
2-(trityloxymethyl)prop-1-yl]-4-penten-1-ol (11). To a solution of
LiBH4 (1.75 g, 0.080 mol) and MeOH (1.75 mL) in THF (20 mL) was
added acyloxazolidinone 10 (9.47 g, 0.011 mol) in THF (50 mL), and
then the reaction solution was stirred at room temperature for 1 h. After
addition of a saturated aqueous NH4Cl solution, the mixture was
concentrated. The residue was dissolved in EtOAc and H2O. The
solution was separated, washed with brine, and dried (Na2SO4).
Concentration followed by silica gel column chromatography (EtOAc/
hexane, 1:3) gave alcohol 11 (6.97 g, 0.0098 mol, 89%) as a colorless
oil: [R]20D -43 (c 0.7, CHCl3); 1H NMR (CDCl3) δ 0.53 (1H, m, CH-
2a), 0.88-1.13 (21H, m, i-Pr), 1.41 (1H, m, CH-2b), 1.49 (1H, m,
H-2), 1.57 (1H, br s, OH), 1.94 (1H, m, H-3a), 2.06 (1H, m, H-3b),
2.31 (1H, m, TrOCH2CH), 2.80 (1H, dd, J ) 9.5, 9.5 Hz, TrOCH2a),
3.13 (1H, dd, J ) 9.5, 5.1 Hz, TrOCH2b), 3.49 (2H, d, J ) 4.9 Hz,
H2-1), 3.73 (3H, s, OCH3), 3.84 (3H, s, OCH3), 4.91-4.97 (2H, m,
H2-5), 5.30 (1H, d, J ) 3.9 Hz, ArCHOSi), 5.65 (1H, m, H-4), 6.60
(2H, s, ArH), 6.87 (1H, s, ArH), 7.23-7.32 (9H, m, ArH), 7.44-7.46
(6H, m, ArH); 13C NMR (CDCl3) δ 12.4, 18.0, 18.1, 26.9, 36.9, 38.2,
44.6, 55.7, 64.7, 74.3, 87.0, 109.9, 110.4, 116.1, 119.4, 127.0, 127.7,
128.7, 134.1, 136.9, 144.2, 147.7, 148.1; anal. C 76.31%, H 8.57%,
7.54%, N 1.66%. (R)-[(4R,5R)]-9: [R]20 +10 (c 1.1, CHCl3).
D
(R)-4-Benzyl-3-[(4S,5S)-5-(3,4-dimethoxyphenyl)-5-(triisopropyl-
silyloxy)-4- (trityloxymethyl)pentanoyl]-2-oxazolidinone (19). Yield
1
83%, colorless oil: [R]20 -42 (c 0.5, CHCl3); H NMR (CDCl3) δ
D
0.98-1.08 (21H, m, i-Pr), 1.15 (1H, m, H-3a of pentanoyl), 1.89 (1H,
m, H-3b of pentanoyl), 2.32 (1H, m, H-4 of pentanoyl), 2.70 (1H, dd,
J ) 13.6, 9.6 Hz, PhCH2a), 2.84-2.98 (1H, overlapped, TrOCH2a),
2.91 (2H, t, J ) 9.0 Hz, H2-2 of pentanoyl), 3.17 (1H, dd, J ) 9.6, 5.7
Hz, TrOCH2b), 3.23 (1H, dd, J ) 13.6, 3.2 Hz, PhCH2b), 3.74 (3H, s,
OCH3), 3.81 (3H, s, OCH3), 4.03-4.10 (2H, m, H2-5), 4.54 (1H, m,
H-4), 5.19 (1H, d, J ) 4.5 Hz, ArCHOSi), 6.59 (2H, s, ArH), 6.88
(1H, s, ArH), 7.15-7.17 (2H, m, ArH), 7.20-7.32 (7H, m, ArH), 7.43-
7.45 (6H, m, ArH); 13C NMR (CDCl3) δ 12.3, 18.0, 18.1, 20.9, 34.1,
37.8, 46.7, 55.1, 55.66, 55.71, 64.4, 65.9, 74.4, 74.5, 86.9, 110.0, 110.2,
119.3, 126.9, 127.2, 127.7, 128.7, 128.9, 129.3, 134.4, 135.3, 144.1,
147.7, 148.2, 153.1, 173.1; anal. C 74.43%, H 7.15%, N 1.60%, calcd
for C52H63O7NSi, C 74.16%, H 7.54%, N 1.66%. (S)-[(4R,5R)]-19:
calcd for C45H60O5Si, C 76.23%, H 8.53%. (R)-[(2R,3R)]-11: [R]20
+43 (c 1.0, CHCl3).
D
(R)-2-[(2S,3S)-3-(3,4-Dimethoxyphenyl)-3-(triisopropylsilyloxy)-
2-(trityloxymethyl)prop-1-yl]-4-penten-1-ol (21). Yield 90%, colorless
oil: [R]20D -24 (c 1.2, CHCl3); 1H NMR (CDCl3) δ 0.60 (1H, m, CH-
2a), 0.99-1.12 (21H, m, i-Pr), 1.36-1.45 (2H, m, CH-2b, H-2), 1.60
(1H, br s, OH), 1.94 (1H, m, H-3a), 2.05 (1H, m, H-3b), 2.36 (1H, m,
TrOCH2CH), 2.80 (1H, dd, J ) 9.5, 9.5 Hz, TrOCH2a), 3.16 (1H, dd,
J ) 9.5, 5.3 Hz, TrOCH2b), 3.34 (1H, dd, J ) 10.8, 5.4 Hz, H-1a),
3.43 (1H, dd, J ) 10.8, 5.4 Hz, H-1b), 3.70 (3H, s, OCH3), 3.81 (3H,
s, OCH3), 4.96-4.99 (2H, m, 5-H2), 5.29 (1H, d, J ) 4.2 Hz,
ArCHOSi), 5.72 (1H, m, 4-H), 6.55-6.58 (2H, m, ArH), 6.84 (1H, s,
ArH), 7.21-7.31 (9H, m, ArH), 7.43-7.46 (6H, m, ArH); 13C NMR
(CDCl3) δ 12.4, 18.0, 18.1, 26.5, 35.4, 38.3, 44.1, 55.67, 55.70, 64.7,
65.8, 74.2, 87.0, 109.9, 110.5, 116.1, 119.5, 127.0, 127.7, 128.7, 134.2,
137.0, 144.1, 147.7, 148.1; anal. C 76.09%, H 8.55%, calcd for
[R]20 +42 (c 0.7, CHCl3).
D
(S)-4-Benzyl-3-{(S)-2-[(2S,3S)-3-(3,4-dimethoxypheyl)-3-(triiso-
propylsilyloxy)-2-(trityloxymethyl)prop-1-yl]-4-pentenoyl}-2-oxazo-
lidinone (10). To a solution of KDMDS (26.7 mL, 0.5 M toluene, 0.013
mol) in THF (80 mL) was added a solution of acyloxazolidinone 9
(18.6 g, 0.022 mol) in THF (50 mL) and allyl bromide (2.83 mL, 0.033
mol) at -70 °C. The solution was gradually warmed to room
temperature for 16 h. After addition of a saturated aqueous NH4Cl
solution, the organic solution was separated, washed with brine, and
dried (Na2SO4). Concentration followed by silica gel column chroma-
tography (EtOAc/hexane, 1:6) gave allyl compound 10 (9.47 g, 0.011
C45H60O5Si, C 76.23%, H 8.53%. (S)-2-[(2R,3R)]-21: [R]20 +24 (c
D
1
mol, 50%) as a colorless oil: [R]20 -25 (c 0.9, CHCl3); H NMR
0.5, CHCl3).
D
(CDCl3) δ 0.90-1.11 (22H, m, i-Pr, CHH-2 of pentenoyl), 2.08 (1H,
m, CHH-2 of pentenoyl), 2.19 (1H, m, HH-3 pentenoyl), 2.26-2.39
(2H, m, HH-3 pentenoyl, TrOCH2CH), 2.56 (1H, dd, J ) 13.2, 10.3
Hz, CH2aPh), 2.79 (1H, dd, J ) 9.3, 9.3 Hz, TrOCH2a), 3.12 (1H, dd,
J ) 9.3, 5.6 Hz, TrOCH2b), 3.29 (1H, dd, J ) 13.2, 2.9 Hz, CH2bPh),
3.71 (3H, s, OCH3), 3.82 (3H, s, OCH3), 3.82-3.89 (1H, overlapped,
H-2 of pentenoyl), 3.95 (1H, dd, J ) 9.3, 8.5 Hz, H-5a), 4.05 (1H, dd,
J ) 9.3, 2.4 Hz, H-5b), 4.52 (1H, m, H-4), 4.93-4.99 (2H, m, H2-5 of
pentenoyl), 5.27 (1H, d, J 3.9 Hz, ArCHOSi), 5.69 (1H, m, H-4 of
(S)-2-[(2S,3S)-3-(3,4-Dimethoxyphenyl)-3-(triisopropylsilyloxy)-
2-(trityloxymethyl)prop-1-yl]-4-pentenal (12). A mixture of alcohol
11 (6.97 g, 0.0098 mol), PCC (2.66 g, 0.012 mol), and molecular sieves
4 Å (0.1 g) in CH2Cl2 (150 mL) was stirred at room temperature for
16 h before addition of dry Et2O. After filtration, the filtrate was
concentrated. The residue was applied to silica gel column chroma-
tography (EtOAc/hexane, 1:5) to give aldehyde 12 (5.21 g, 0.0074 mol,
76%) as colorless crystals, mp 98-99 °C (i-Pr2O): [R]20D -29 (c 1.2,
1
CHCl3); H NMR (CDCl3) δ 0.79 (1H, m CH-2a), 0.92-1.10 (21H,

554 Journal of Natural Products, 2007, Vol. 70, No. 4
Yamauchi et al.
m, i-Pr), 1.88 (1H, m, CH-2b), 2.10 (1H, m, TrOCH2CH), 2.22-2.31
(3H, m, H-2, H2-3), 2.81 (1H, dd, J ) 9.3, 9.3 Hz, TrOCH2a), 3.11
(1H, dd, J ) 9.3, 5.4 Hz, TrOCH2b), 3.71 (3H, s, OCH3), 3.82 (3H, s,
OCH3), 4.93-4.97 (2H, m, H2-5), 5.23 (1H, d, J ) 4.4 Hz, ArCHOSi),
5.58 (1H, m, H-4), 6.57 (2H, s, ArH), 6.82 (1H, s, ArH), 7.21-7.32
(9H, m, ArH), 7.40-7.43 (6H, m, ArH), 9.46 (1H, d, J ) 2.9 Hz,
CHO); 13C NMR (CDCl3) δ 12.3, 12.5, 17.9, 18.0, 18.1, 25.6, 34.1,
44.7, 49.1, 55.7, 55.8, 64.1, 74.3, 87.0, 110.0, 110.2, 117.1, 119.3, 127.0,
127.2, 127.7, 127.9, 128.6, 133.9, 134.7, 144.0, 146.9, 147.8, 148.2,
204.5; anal. C 76.46%, H 8.29%, calcd for C45H58O5Si, C 76.44%, H
Hz, ArH), 6.91 (1H, d, J ) 2.0 Hz, ArH); 13C NMR (CDCl3) δ 12.6,
18.0, 18.1, 21.2, 28.0, 34.9, 40.9, 46.4, 55.79, 55.82, 55.86, 63.6, 77.6,
79.5, 110.0, 110.4, 110.6, 117.2, 119.3, 119.5, 131.5, 135.8, 136.0,
148.3, 148.5, 148.7, 170.0; anal. C 67.01%, H 8.74%, calcd for
C36H56O8Si, C 67.05%, H 8.75%. (1R,2R,4R)-4-[(R)]-15, [R]20 +52
D
(c 0.7, CHCl3).
(1S,2R)-1-(3,4-Dimethoxyphenyl)-2-[(2S,3S)-3-(3,4-dimethoxyphe-
nyl)-3-(triisopropylsilyloxy)-2-(trityloxymethyl)prop-1-yl]-4-penten-
1-ol (23) and (1R,2R)-1-(3,4-Dimethoxyphenyl)-2-[(2S,3S)-3-(3,4-
dimethoxyphenyl)-3-(triisopropylsilyloxy)-2-(trityloxymethyl)prop-
1-yl]-4-penten-1-ol (24). To a solution of 3,4-dimethoxyphenylmagnesium
bromide (18 mL, 0.5 M in THF, 9.00 mmol) in THF (20 mL) was
added aldehyde 22 (2.96 g, 4.19 mmol) in THF (40 mL) at 0 °C. After
the reaction solution was stirred at room temperature for 1 h, a saturated
aqueous NH4Cl solution was added. The organic solution was separated,
washed with brine, and dried (Na2SO4). Concentration followed by silica
gel column chromatography (10% EtOAc in toluene) gave 23 (0.98 g,
1.16 mmol, 28%) as a colorless oil and 24 (0.92 g, 1.09 mmol, 26%)
as a colorless oil. 23: [R]20D -26 (c 1.5, CHCl3); 1H NMR (CDCl3) δ
0.48 (1H, m, CH-2a), 0.96-1.05 (21H, m, i-Pr), 1.44 (1H, m, CH-2b),
1.53 (1H, m, H-2), 1.89 (1H, br s, OH), 2.05 (1H, m, H-3a), 2.20 (1H,
m, H-3b), 2.31 (1H, m, TrOCH2CH), 2.67 (1H, dd, J ) 9.3, 9.3 Hz,
TrOCH2a), 3.01 (1H, dd, J ) 9.3, 5.2 Hz, TrOCH2b), 3.66 (3H, s,
OCH3), 3.68 (3H, s, OCH3), 3.80 (3H, s, OCH3), 3.83 (3H, s, OCH3),
4.42 (1H, d, J ) 6.2 Hz, ArCHOH), 5.04-5.10 (2H, m, CH2dCH),
5.17 (1H, d, J ) 4.2 Hz, ArCHOSi), 5.82 (1H, m, CH2dCH), 6.43-
6.53 (2H, m, ArH), 6.57-6.65 (2H, m, ArH), 6.69 (1H, d, J ) 8.5 Hz,
ArH), 6.76 (1H, d, J ) 1.6 Hz, ArH), 7.20-7.30 (9H, m, ArH), 7.39-
7.43 (6H, m, ArH); 13C NMR (CDCl3) δ 12.4, 18.0, 18.1, 26.1, 33.8,
42.9, 44.9, 55.66, 55.71, 55.74, 64.4, 74.4, 75.7, 87.0, 100.6, 105.7,
109.4, 109.8, 110.3, 110.6, 116.2, 118.6, 119.3, 126.9, 127.7, 128.6,
134.4, 135.5, 137.3, 144.1, 147.6, 148.0, 148.5; anal. C 75.08%, H
8.08%, calcd for C53H68O7Si, C 75.32%, H 8.11%. (1R,2S)-2-[(2R,3R)]-
8.27%. (R)-[(2R,3R)]-12: [R]20 +28 (c 0.7, CHCl3).
D
(R)-2-[(2S,3S)-3-(3,4-Dimethoxyphenyl)-3-(triisopropylsilyloxy)-
2-(trityloxymethyl)prop-1-yl]-4-pentenal (22). Yield 100%, colorless
oil: [R]20D -30 (c 1.2, CHCl3); 1H NMR (CDCl3) δ 0.88-1.56 (22H,
m, i-Pr, CH2a-3), 1.53 (1H, m, CH2b-3), 2.17 (1H, m, H-3a), 2.26 (1H,
m, H-3b), 2.31-2.38 (2H, m, H-2, TrOCH2CH), 2.83 (1H, dd, J )
9.4, 9.4 Hz, TrOCH2a), 3.11 (1H, dd, J ) 9.7, 5.5 Hz, TrOCH2b), 3.71
(3H, s, OCH3), 3.82 (3H, s, OCH3), 4.99-5.03 (2H, m, H2-5), 5.28
(1H, d, J ) 4.2 Hz, ArCHOSi), 5.67 (1H, m, H-4), 6.58 (2H, s, ArH),
6.82 (1H, s, ArH), 7.21-7.32 (9H, m, ArH), 7.42-7.44 (6H, m, ArH),
9.47 (1H, d, J ) 2.1 Hz, CHO); 13C NMR (CDCl3) δ 12.3, 17.95,
18.04, 24.7, 33.1, 44.6, 49.3, 55.6, 64.1, 74.1, 86.9, 110.0, 110.2, 117.0,
119.3, 126.9, 127.1, 127.7, 127.79, 127.80, 128.5, 133.8, 134.8, 143.9,
146.8, 147.7, 148.1, 204.4; anal. C 76.64%, H 8.01%, calcd for
C45H58O5Si, C 76.44%, H 8.27%. (S)-2-[(2R,3R)]-22: [R]20 +31 (c
D
0.8, CHCl3).
(1R,2S,4S)-2-Allyl-5-hydroxy-1-(3,4-dimethoxyphenyl)-4-[(S)-(3,4-
dimethoxyphenyl)(triisopropylsilyloxy)methyl]pentyl Acetate (14)
and (1S,2S,4S)-2-Allyl-5-hydroxy-1-(3,4-dimethoxyphenyl)-4-[(S)-
(3,4-dimethoxyphenyl)(triisopropylsilyloxy)methyl]pentyl Acetate
(15). A mixture of Mg (6.08 g, 0.25 mol) and 1-bromo-3,4-dimethoxy-
benzene (5.07 mL, 35.3 mmol) in THF (150 mL) was heated under
reflux for 1 h before aldehyde 12 (1.98 g, 2.80 mmol) in THF (50 mL)
was added at 0 °C. After stirring at room temperature for 1 h, a saturated
aqueous NH4Cl solution was added. The solution was separated, washed
with brine, and dried (Na2SO4). Concentration followed by silica gel
column chromatography (10% EtOAc/toluene and EtOAc/hexane, 1:1)
gave Grignard product 13 (2.21 g, 2.61 mmol, 93%) as a diastereomeric
mixture (found C, 75.38; H, 8.19; C53H68O7Si requires C, 75.32; H,
8.11). A solution of Grignard product (2.21 g, 2.61 mmol) in pyridine
(7 mL) and Ac2O (7 mL) was stirred at room temperature for 16 h,
and then ice was added. After 6 h, the mixture was dissolved in CHCl3
and H2O. The organic solution was separated, washed with 1 M aqueous
HCl solution, saturated aqueous NaHCO3 solution, and brine, and dried
(Na2SO4). Concentration gave a crude acetate. To a solution of the
crude acetate in ether (24 mL) was added HCO2H (36 mL) at -5 °C.
After stirring at -5 °C for 10 min, CHCl3 and H2O were added. The
organic solution was separated, washed with a saturated aqueous
NaHCO3 solution and brine, and dried (Na2SO4). Concentration
followed by silica gel column chromatography (EtOAc/hexane, 1:1)
gave acetate 14 (0.64 g, 0.99 mmol, 35%) as a colorless oil and acetate
1
23: [R]20 +26 (c 0.3, CHCl3). 24: [R]20 -12 (c 1.3, CHCl3); H
D
D
NMR (CDCl3) δ 0.67 (1H, m, CH-2a), 0.96-1.13 (21H, m, i-Pr), 1.51-
1.60 (2H, m, CH-2b, H-2), 1.90-2.14 (2H, m, OH, H-3a), 2.12 (1H,
m, H-3b), 2.33 (1H, m, TrOCH2CH), 2.47 (1H, dd, J ) 9.6, 4.4 Hz,
TrOCH2a), 2.88 (1H, d, J ) 9.6, 4.4 Hz, TrOCH2b), 3.63 (3H, s, OCH3),
3.68 (3H, s, OCH3), 3.80 (3H, s, OCH3), 3.82 (3H, s, OCH3), 4.51
(1H, d, J ) 4.2 Hz, ArCHOH), 4.93-5.01 (2H, m, CH2dCH), 5.26
(1H, d, J ) 3.7 Hz, ArCHOSi), 5.77 (1H, m, CH2dCH), 6.44-6.52
(3H, m, ArH), 6.57 (1H, d, J ) 8.2 Hz, ArH), 6.62 (1H, d, J ) 1.8 Hz,
ArH), 6.79 (1H, s, ArH), 7.21-7.29 (9H, m, ArH), 7.35-7.37 (6H,
m, ArH); 13C NMR (CDCl3) δ 12.4, 18.0, 18.1, 24.2, 35.2, 43.6, 44.8,
55.6, 55.7, 64.2, 74.1, 75.4, 86.8, 109.3, 109.8, 110.5, 116.2, 118.4,
119.4, 126.9, 127.6, 128.7, 134.1, 136.0, 137.2, 144.1, 147.6, 147.8,
147.9, 148.6; anal. C 75.21%, H 8.09%, calcd for C53H68O7Si, C
75.32%, H 8.11%. (1S,2S)-2-[(2R,3R)]-24: [R]20D +12 (c 0.3, CHCl3).
(1S,2R,4S)-2-Allyl-5-hydroxy-1-(3,4-dimethoxyphenyl)-4-[(S)-(3,4-
dimethoxyphenyl)(triisopropylsilyloxy)methyl]pentyl Acetate (25).
A solution of Grignard product 23 (0.86 g, 1.02 mmol) in pyridine (5
mL) and Ac2O (5 mL) was stirred at room temperature for 16 h, and
then ice was added. After 6 h, the mixture was dissolved in CHCl3 and
H2O. The organic phase was separated, washed with 1 M aqueous HCl
solution, a saturated aqueous NaHCO3 solution, and brine, and dried
(Na2SO4). Concentration gave a crude acetate. To a solution of the
crude acetate in ether (10 mL) was added HCO2H (15 mL) at -5 °C.
After stirring at -5 °C for 10 min, CHCl3 and H2O were added. The
organic solution was separated, washed with a saturated aqueous
NaHCO3 solution and brine, and dried (Na2SO4). Concentration
followed by silica gel column chromatography (EtOAc/hexane, 1:1)
15 (0.68 g, 1.05 mmol, 38%) as a colorless oil. 14: [R]20 -2 (c 1.6,
D
1
CHCl3); H NMR (CDCl3) δ 0.95-1.00 (21H, m, i-Pr), 1.11 (1H, m,
CH2aCHCH2OH), 1.42 (1H, m, CH2bCHCH2OH), 1.73 (1H, m, Ar-
(AcO)CHCH), 1.90 (1H, m, CH2dCHCH2a), 1.96 (3H, s, Ac), 2.01
(1H, m, CH2dCHCH2b), 2.16 (1H, m, HOCH2CH), 2.85 (1H, br s,
OH), 3.61 (1H, m, HOCH2a), 3.84-3.92 (1H, overlapped, HOCH2b),
3.84 (3H, s, OCH3), 3.85 (3H, s, OCH3), 3.87 (3H, s, OCH3), 3.88
(3H, s, OCH3), 4.64 (1H, d, J ) 5.9 Hz, ArCHOAc), 4.97-5.02 (2H,
m, CH2dCH), 5.64 (1H, d, J ) 5.9 Hz, ArCHOSi), 5.69 (1H, m, CH2d
CH), 6.68-6.70 (3H, m, ArH), 6.76-6.78 (2H, m, ArH), 6.82 (1H, d,
J 2.0 Hz, ArH); 13C NMR (CDCl3) δ 12.5, 17.9, 18.0, 20.8, 28.4, 34.2,
41.0, 45.9, 55.68, 55.74, 55.8, 62.9, 76.3, 80.2, 109.7, 110.3, 110.8,
116.7, 118.7, 119.1, 132.0, 136.0, 136.4, 148.2, 148.3, 148.6, 148.7,
169.8; anal. C 67.01%, H 8.66%, calcd for C36H56O8Si, C 67.05%, H
gave alcohol 25 (0.38 g, 0.59 mmol, 58%) as a colorless oil: [R]20
D
1
+4 (c 0.5, CHCl3); H NMR (CDCl3) δ 0.91-0.93 (21H, m, i-Pr),
1.01 (1H, m, H-3a), 1.16 (1H, m, H-3b), 1.80 (1H, m, H-2), 1.98-
2.07 (1H, overlapped, CH2dCH-CH2a), 2.02 (3H, s, Ac), 2.19 (1H,
m, H-4), 2.20 (1H, m, CH2dCH-CH2b), 2.68 (1H, br s, OH), 3.45
(1H, m, H-5a), 3.69 (1H, m, H-5b), 3.858 (3H, s, OCH3), 3.864 (3H,
s, OCH3), 3.87 (3H, s, OCH3), 3.88 (3H, s, OCH3), 4.67 (1H, d, J )
5.9 Hz, H-1), 4.87-4.99 (2H, m, CH2dCH), 5.51 (1H, d, J ) 8.3 Hz,
ArCHOSi), 5.62 (1H, m, CH2dCH), 6.73-6.86 (6H, m, ArH); anal.
C 66.92%, H 8.63%, calcd for C36H56O8Si, C 67.05%, H 8.75%.
(1R,2R,4S)-2-Allyl-5-hydroxy-1-(3,4-dimethoxyphenyl)-4-[(S)-
8.75%. (1S,2R,4R)-4-[(R)]-14: [R]20 +2 (c 0.6, CHCl3). 15: [R]D
20
D
1
-52 (c 0.6, CHCl3); H NMR (CDCl3) δ 0.96-1.01 (21H, m, i-Pr),
1.30-1.39 (2H, m, CH2CHCH2OH), 1.79 (1H, m, Ar(AcO)CHCH),
1.89 (1H, m, HOCH2CH), 1.96 (1H, m, CH2dCHCH2a), 2.01 (3H, s,
Ac), 2.17 (1H, m, CH2dCHCH2b), 3.60 (1H, dd, J ) 11.0, 6.1 Hz,
HOCH2a), 3.78-3.89 (1H, overlapped, HOCH2b), 3.84 (3H, s, OCH3),
3.86 (3H, s, OCH3), 3.88 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.75
(1H, d, J ) 5.9 Hz, ArCHOAc), 4.93-5.04 (2H, m, CH2dCH), 5.56
(1H, d, J ) 6.4 Hz, ArCHOSi), 5.71 (1H, m, CH2dCH), 6.55 (1H, dd,
J ) 8.3, 2.0 Hz, ArH), 6.68-6.73 (3H, m, ArH), 6.77 (1H, d, J ) 8.3
(3,4-dimethoxyphenyl)(triisopropylsilyloxy)methyl]pentyl Acetate
1
(26). Yield 59%, colorless oil: [R]20 +15 (c 0.8, CHCl3); H NMR
D
(CDCl3) δ 0.92-1.02 (21H, m, i-Pr), 1.24 (1H, m, CH-2a), 1.46 (1H,

Stereochemistry of Tetrahydropyran Sesquineolignans
Journal of Natural Products, 2007, Vol. 70, No. 4 555
m, CH-2b), 1.77 (1H, m, H-2), 1.82-2.00 (3H, m, H-4, CH2dCHCH2),
2.04 (3H, s, Ac), 2.86 (1H, br dd, J ) 6.1, 6.1 Hz, OH), 3.53 (1H, m,
H-5a), 3.74 (1H, m, H-5b), 3.86 (6H, s, OCH3), 3.89 (6H, s, OCH3),
4.76-4.80 (2H, m, CH2dCH), 4.91 (1H, d, J ) 10.0 Hz, ArCHOAc),
5.52 (1H, m, CH2dCH), 5.56 (1H, d, J ) 7.3 Hz, ArCHOSi), 6.77-
6.84 (5H, m, ArH), 6.93 (1H, s, ArH); 13C NMR (CDCl3) δ 12.5, 17.9,
18.0, 21.2, 27.5, 34.1, 40.6, 46.2, 55.79, 55.84, 55.88, 62.9, 77.8, 80.0,
109.9, 110.1, 110.4, 110.8, 117.1, 119.3, 119.5, 131.8, 134.9, 135.9,
148.4, 148.6, 148.7, 148.8, 170.2; anal. C 66.85%, H, 8.45%, calcd
for C36H56O8Si, C 67.05%, H 8.75%. (1S,2S,4R)-4-[(R)]-26: [R]20D -15
(c 0.4, CHCl3).
110.7, 116.3, 119.4, 119.9, 134.1, 135.5, 137.0, 148.4, 148.6, 148.9,
149.0; anal. C 69.99%, H 9.04%, calcd for C34H52O6Si, C 69.82%, H
8.96%. (2R,3R,5R)-5-[(R)]-17: [R]20 +11 (c 0.6, CHCl3).
D
(2R,3R,5S)-3-Allyl-2-(3,4-dimethoxyphenyl)-5-[(S)-(3,4-dimethox-
yphenyl)(triisopropylsilyloxy)methyl]tetrahydropyran (28). Yield
1
54%, colorless oil: [R]20 -19 (c 0.3, CHCl3); H NMR (CDCl3) δ
D
0.95-1.03 (21H, m, i-Pr), 1.58-1.66 (4H, m, H-3 (H-8), H2-4 (H2-9),
CH2dCHCH2a), 1.82 (1H, m, CH2dCHCH2b), 2.10 (1H, m, H-5 (H-
8′)), 3.32 (1H, dd, J ) 11.0, 11.0, H-6a (H-9′a)), 3.77 (1H, d, J ) 9.3
Hz, H-2 (H-7)), 3.86 (3H, s, OCH3), 3.87 (3H, s, OCH3), 3.88 (3H, s,
OCH3), 3.89 (3H, s, OCH3), 4.39 (1H, br d, J ) 11.0 Hz, H-6b (H-
9′b)), 4.48 (1H, d, J ) 7.3 Hz, ArCHOSi), 4.79-4.88 (2H, m, CH2d
CH), 5.51 (1H, m, CH2dCH), 6.75 (1H, dd, J ) 8.2, 1.7 Hz, ArH),
6.78-6.84 (4H, m, ArH), 6.90 (1H, d, J ) 1.5 Hz, ArH); 13C NMR
(CDCl3) δ 12.5, 18.1, 32.2, 36.5, 41.0, 45.1, 55.8, 71.5, 77.4, 85.3,
109.7, 109.8, 110.2, 110.8, 116.2, 119.1, 120.1, 133.5, 135.6, 136.0,
148.2, 148.6, 148.7, 149.0; anal. C 69.54%, H 8.95%, calcd for
(2R,3S,5S)-3-Allyl-2-(3,4-dimethoxyphenyl)-5-[(S)-(3,4-dimethox-
yphenyl)(triisopropylsilyloxy)methyl]tetrahydropyran (16). To an
ice-cooled solution of alcohol 14 (0.35 g, 0.54 mmol) and Et3N (84
µL, 0.60 mmol) in CH2Cl2 (1 mL) was added MsCl (46 µL, 0.59 mmol),
and then the reaction mixture was stirred at 0 °C for 30 min. After
addition of CH2Cl2 and H2O, the organic solution was separated, washed
with saturated aqueous NaHCO3 and brine, and dried (Na2SO4).
Concentration gave a crude mesylate. A mixture of the crude mesylate
and K2CO3 (0.32 g, 2.32 mmol) in MeOH (5 mL) was stirred at room
temperature for 6 h, and then H2O and EtOAc were added. The organic
phase was separated, washed with brine, and dried (Na2SO4). Concen-
tration gave a crude hydroxy mesylate. To a suspension of NaH (0.10
g, 60% oil suspension, 2.50 mmol) in DMF (5 mL) was added a solution
of the crude hydroxy mesylate in DMF (1 mL) at 0 °C. After stirring
at room temperature for 16 h, EtOAc and H2O were added. The organic
phase was separated, washed with brine, and dried (Na2SO4). Concen-
tration followed by silica gel column chromatography (EtOAc/hexane,
1:4) gave tetrahydropyran 16 (0.22 g, 0.38 mmol, 70%) as a colorless
oil: [R]20D +6 (c 0.8, CHCl3); 1H NMR (CDCl3) δ 0.88 (1H, m, H-4a
(H-9a)), 0.94-1.01 (21H, m, i-Pr), 1.32 (1H, m, H-4b (H-9b)), 1.74
(1H, m, H-3 (H-8)), 1.82 (1H, m, CH2dCHCH2a), 2.00 (1H, m, CH2d
CHCH2b), 2.20 (1H, m, H-5 (H-8′)), 3.42 (1H, dd, J ) 11.2, 11.2 Hz,
H-6a (H-9′a)), 3.86 (3H, s, OCH3), 3.87 (3H, s, OCH3), 3.877 (3H, s,
OCH3), 3.882 (3H, s, OCH3), 4.42 (1H, d, J ) 7.3 Hz, ArCHOSi),
4.45 (1H, d, J ) 2.0 Hz, H-2 (H-7)), 4.51 (1H, dd, J ) 11.2, 2.4 Hz,
H-6b (H-9′b)), 4.74-4.82 (2H, m, CH2dCH), 5.35 (1H, m, CH2dCH),
6.72 (1H, dd, J ) 8.1, 2.0 Hz, ArH), 6.74-6.84 (4H, m, ArH), 6.87
(1H, d, J ) 2.0 Hz, ArH); anal. C 69.79%, H 8.98%, calcd for C34H52O6-
Si, C 69.82%, H 8.96%.
C34H52O6Si, C 69.82%, H 8.96%. (2S,3S,5R)-5-[(R)]-28: [R]20 +19
D
(c 0.2, CHCl3).
(2S,3S,5S)-3-(3,4-Dimethoxycinnamyl)-2-(3,4-dimethoxyphenyl)-
5-[(S)-(3,4- dimethoxyphenyl)(triisopropylsilyloxy)methyl]tetrahydro-
pyran (18). A reaction solution of olefin 17 (0.21 g, 0.36 mmol),
1-bromo-3,4-dimethoxybenzene (0.17 g, 0.78 mmol), Et3N (0.23 mL,
1.65 mmol), and PdCl2(PPh3)2 (35 mg, 0.050 mmol) in DMF (0.5 mL)
was heated at 90 °C under N2 gas for 6 h before addition of H2O and
EtOAc. The organic solution was separated, washed with brine, and
dried (Na2SO4). Concentration followed by silica gel column chroma-
tography (EtOAc/hexane, 1:6 and 1:1) gave recovered olefin 17 (0.15
g, 0.21 mmol, 58%) and cinnamyl 18 (88 mg, 0.12 mmol, 33%) as a
1
colorless oil: [R]20 +38 (c 0.5, CHCl3); H NMR (CDCl3) δ 0.88-
D
1.08 (22H, m, i-Pr, H-4a (H-9a)), 1.29 (1H, m, H-4b (H-9b)), 1.65
(1H, m, H-3 (H-8)), 1.72-1.82 (2H, m, ArCHdCHCH2), 1.95 (1H,
m, H-5 (H-8′)), 3.69 (1H, dd, J ) 11.5, 2.7 Hz, H-6a (H-9′a)), 3.74
(3H, s, OCH3), 3.82 (3H, s, OCH3), 3.847 (3H, s, OCH3), 3.850 (3H,
s, OCH3), 3.89 (3H, s, OCH3), 3.92 (3H, s, OCH3), 3.97 (1H, d, J )
9.3 Hz, H-2 (H-7)), 4.60 (1H, d, J ) 1l.5 Hz, H-6b (H-9′b)), 5.10 (1H,
d, J ) 10.3 Hz, ArCHOSi), 5.65 (1H, m, ArCHdCHCH2), 6.04 (1H,
d, J ) 16.1 Hz, ArCHdCHCH2), 6.58 (1H, d, J ) 8.3 Hz, ArH), 6.65-
6.66 (2H, m, ArH), 6.68-6.78 (2H, m, ArH), 6.84-6.92 (3H, m, ArH),
6.97 (1H, d, J ) 1.6 Hz, ArH); 13C NMR (CDCl3) δ 12.6, 18.0, 18.1,
31.1, 35.4, 39.2, 43.8, 55.6, 55.7, 55.79, 55.83, 55.9, 68.5, 73.9, 85.8,
108.6, 110.2, 110.8, 111.1, 118.6, 119.4, 120.0, 125.7, 130.8, 131.0,
134.1, 136.9, 148.29, 148.31, 148.67, 148.9, 149.0; anal. C 69.73%,
H 8.41%, calcd for C42H60O8Si, C 69.97%, H 8.39%. (2R,3R,5R)-5-
(2S,3R,5S)-3-Allyl-2-(3,4-dimethoxyphenyl)-5-[(S)-(3,4-dimethox-
yphenyl)(triisopropylsilyloxy)methyl]tetrahydropyran (27). Yield
1
95%, colorless oil: [R]20 +54 (c 1.3, CHCl3); H NMR (CDCl3) δ
D
0.94-1.01 (21H, m, i-Pr), 1.44 (1H, m, H-4a (H-9a)), 1.68 (1H, m,
H-4b (H-9b)), 1.84-1.95 (2H, m, H-3 (H-8), H-5 (H-8′)), 1.95-2.11
(2H, m, CH2dCHCH2), 3.79-3.83 (1H, overlapped, H-6a (H-9a)), 3.81
(3H, s, OCH3), 3.868 (3H, s, OCH3), 3.872 (3H, s, OCH3), 3.88 (3H,
s, OCH3), 4.01 (1H, dd, J ) 11.2, 7.3 Hz, H-6b (H-9′b)), 4.66 (1H, d,
J ) 4.9 Hz, H-2 (H-7)), 4.71 (1H, d, J ) 8.3 Hz, ArCHOSi), 4.73-
4.82 (2H, m, CH2dCH), 5.48 (1H, m, CH2dCH), 6.78-6.80 (3H, m,
ArH), 6.84-6.85 (2H, m, ArH), 6.90 (1H, s, ArH); anal. C 69.94%, H
8.92%, calcd for C34H52O6Si, C 69.82%, H 8.96%.
[(R)]-18: [R]20 -37 (c 0.4, CHCl3).
D
(2S,3S,5S)-5-[(S)-(Hydroxy)(3,4-dimethoxyphenyl)methyl]-3-(3,4-
dimethoxycinnamyl)-2-(3,4-dimethoxyphenyl)tetrahydropyran [(+)-
morinol B]. A solution of silyl ether (88 mg, 0.12 mmol) and TBAF
(0.21 mL, 1 M in THF, 0.21 mmol) in THF (2 mL) was stirred at
room temperature for 3 h before addition of a saturated aqueous NH4-
Cl solution and EtOAc. The solution was separated, washed with a
saturated aqueous CuSO4 solution, NaHCO3 solution, and brine, and
dried (Na2SO4). Concentration followed by silica gel column chroma-
tography (EtOAc/hexane, 4:1) gave (+)-morinol B (51 mg, 0.12 mmol,
100%) as a colorless oil: [R]20D +69 (c 0.7, CHCl3). NMR data agreed
with that of described morinol B.1,2 HPLC, DAICEL chiral column
OD-H, detected at 272 nm, 1 mL min-1, 50% i-PrOH in hexane, tR 19
min, >99% ee. (-)-Morinol B: [R]D20 -69 (c1.0, CHCl3), tR 28 min,
>99% ee.
(2S,3S,5S)-3-Allyl-2-(3,4-dimethoxyphenyl)-5-[(S)-(3,4-dimethox-
yphenyl)(triisopropylsilyloxy)methyl]tetrahydropyran (17). To an
ice-cooled solution of alcohol 15 (0.22 g, 0.34 mmol) and Et3N (53
µL, 0.38 mmol) in CH2Cl2 (1 mL) was added MsCl (29 µL, 0.37 mmol),
and then the reaction mixture was stirred at 0 °C for 30 min. After
addition of CH2Cl2 and H2O, the organic phase was separated, washed
with a saturated aqueous NaHCO3 and brine, and dried (Na2SO4).
Concentration gave a crude mesylate. A mixture of the crude mesylate
and K2CO3 (0.40 g, 2.89 mmol) in MeOH (5 mL) was stirred at room
temperature for 16 h, and then H2O and EtOAc were added. The organic
phase was separated, washed with brine, and dried (Na2SO4). Concen-
tration followed by silica gel column chromatography (EtOAc/hexane,
1:4) gave tetrahydropyran 17 (0.11 g, 0.19 mmol, 56%) as a colorless
oil: [R]20D -10 (c 0.8, CHCl3); 1H NMR (CDCl3) δ 0.95-1.05 (21H,
m, i-Pr), 1.23 (1H, m, H-4a (H-9a)), 1.38 (1H, m, H-4b (H-9b)), 1.52
(1H, m, H-3 (H-8)), 1.74 (1H, m, CH2dCHCH2a), 1.78-1.83 (2H, m,
CH2dCHCH2b, H-5 (H-8′)), 3.66 (1H, dd, J ) 11.5, 2.7 Hz, H-6a (H-
9′a)), 3.88 (6H, s, OCH3), 3.89 (3H, s, OCH3), 3.91 (3H, s, OCH3),
3.91-3.94 (1H, overlapped, H-2 (H-7)), 4.59 (1H, br d, J ) 11.5 Hz,
H-6b (H-9′b)), 4.75-4.81 (2H, m, CH2dCH), 5.08 (1H, d, J ) 10.3
Hz, ArCHOSi), 5.40 (1H, m, CH2dCH), 6.77-6.91 (4H, m, ArH),
6.93-6.94 (2H, m, ArH); 13C NMR (CDCl3) δ 12.6, 17.9, 18.1, 30.6,
36.4, 38.1, 43.7, 55.7, 55.8, 55.86, 55.88, 68.5, 74.0, 85.7, 109.6, 110.1,
(2R,3R,5S)-3-Allyl-5-[(S)-(hydroxy)(3,4-dimethoxyphenyl)methyl]-
2-(3,4- dimethoxyphenyl)tetrahydropyran (29). Yield 94%, a color-
less oil: [R]20D -5 (c 0.7, CHCl3); 1H NMR (CDCl3) δ 1.00 (1H, ddd,
J ) 12.1, 12.1, 12.1 Hz, H-4a (H-9a)), 1.56-1.71 (3H, m, H-3 (H-8),
H-4b (H-9b), CH2dCHCH2a), 1.82 (1H, m, CH2dCHCH2b), 1.95 (1H,
br s, OH), 2.15 (1H, m, H-5 (H-8′)), 3.37 (1H, dd, J ) 11.2, 11.2,
H-6a (H-9′a)), 3.81 (1H, d, J ) 9.6 Hz, H-2 (H-7)), 3.85 (3H, s, OCH3),
3.87 (3H, s, OCH3), 3.88 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.33
(1H, d, J ) 7.9 Hz, ArCHOH), 4.40 (1H, dd, J ) 11.2, 2.3 Hz, H-6b
(H-9′b)), 4.79-4.89 (2H, m, CH2dCH), 5.50 (1H, m, CH2dCH), 6.79-
6.90 (6H, m, ArH); 13C NMR (CDCl3) δ 32.5, 36.4, 41.0, 43.3, 55.8,
55.9, 71.1, 85.2, 109.3, 110.2, 110.8, 116.3, 118.7, 120.1, 133.4, 135.4,
135.5, 148.6, 148.7, 148.95, 149.0; HREIMS m/z 428.2197 (calcd for
C25H32O6, 428.2198). (2S,3S,5R)-5-[(R)]-29: [R]20D +5 (c 0.6, CHCl3).
(2R,3R,5S)-5-[(S)-(Hydroxy)(3,4-dimethoxyphenyl)methyl]-3-(3,4-
dimethoxycinnamyl)-2-(3,4-dimethoxyphenyl)tetrahydropyran [(-)-

556 Journal of Natural Products, 2007, Vol. 70, No. 4
Yamauchi et al.
Morinol A]. Recovered olefin 29 (67%) and (-)-morinol A (31%) as
109.2, 110.4, 110.8, 110.9, 111.0, 111.2, 118.6, 118.9, 120.2, 125.8,
130.8, 131.3, 133.5, 135.3, 148.4, 148.9, 149.05, 149.1, 149.3; HREIMS
m/z 564.2725 (calcd for C25H32O6, 564.2724).
a colorless oil: [R]20 -15 (c 0.4, CHCl3); NMR data agreed with
D
those of naturally occurring morinol A. HPLC, DAICEL chiral column
OD-H, detected at 272 nm, 1 mL min-1, 50% i-PrOH in hexane, tR 41
min, >99% ee. (+)-Morinol A: [R]20D +15 (c 0.6, CHCl3), tR 34 min,
>99% ee.
(2R,3R,5R)-5-[(S)-(Hydroxy)(3,4-dimethoxyphenyl)methyl]-3-
(3,4-dimethoxycinnamyl)-2-(3,4-dimethoxyphenyl)tetrahydropyr-
an [(+)-7′,8′-erythro-morinol B] (32): colorless oil; [R]20D +34 (c 0.4,
1
(S)-4-Benzyl-3-{(S)-2-[(S)-(hydroxy)(3,4-dimethoxyphenyl)methyl]-
5-hexenoyl}-2-oxazolidinone (30). To a solution of oxazolidinone 3
(10.6 g, 0.039 mol) in CH2Cl2 (150 mL) were added Bu2BOTf (48.6
mL, 1 M in CH2Cl2, 0.049 mol) and Et3N (6.30 mL, 0.045 mol) below
0 °C. After cooling to -65 °C, a solution of 3,4-dimethoxybenzaldehyde
(7.61 g, 0.046 mol) in CH2Cl2 (50 mL) was added. The solution was
stirred at -65 °C for 20 min and warmed to 0 °C. After stirring at 0
°C for 1 h, phosphate buffer (50 mL), MeOH (140 mL), and 2:1 MeOH/
30% H2O2 (140 mL) were added, and the mixture was stirred at 0 °C
for 1 h. The resulting mixture was concentrated at 30 °C. The residue
was dissolved in EtOAc and H2O. The organic phase was separated,
washed with saturated aqueous NaHCO3 and brine, and dried (Na2-
SO4). Concentration followed by silica gel column chromatography
(EtOAc/hexane, 1:3 and 1:1) gave syn product 30 (17.1 g, 0.039 mol,
100%) as a colorless oil: [R]20D +81 (c 0.3, CHCl3); 1H NMR (CDCl3)
δ 1.87 (1H, m, H-3a of hexenoyl), 2.00-2.09 (3H, m, H-3b and H2-4
of hexenoyl), 2.61-2.64 (1H, overlapped, PhCH2a), 2.61 (1H, d, J )
2.9 Hz, OH), 3.23 (1H, d, J ) 13.2 Hz, PhCH2b), 3.71 (1H, dd, J )
8.8, 8.8 Hz, H-5a), 3.80 (3H, s, OCH3), 3.84 (3H, s, OCH3), 3.97 (1H,
d, J ) 8.8 Hz, H-5b), 4.28-4.38 (2H, m, 2-H of hexenoyl, H-4), 4.78
(1H, br s, ArCHOH), 4.91-5.00 (2H, m, H2-6 of hexenoyl), 5.74 (1H,
m, H-5 of hexenoyl), 6.75 (1H, d, J ) 8.3 Hz, ArH), 6.84 (1H, d, J )
8.3 Hz, ArH), 6.95 (1H, s, ArH), 7.14-7.16 (2H, m, ArH), 7.21-7.30
(3H, m, ArH); 13C NMR (CDCl3) δ 27.2, 31.7, 37.9, 49.9, 55.7, 55.8,
55.9, 65.9, 75.1, 109.3, 110.7, 115.2, 118.5, 127.3, 128.9, 129.3, 134.2,
135.2, 137.9, 148.5, 148.8, 153.1, 174.8; anal. C 68.10%, H 6.57%, N
3.00%, calcd for C25H29O6N, C 68.32%, H 6.65%, N 3.19%.
CHCl3); H NMR (CDCl3) δ 1.51 (1H, m, H-4a (H-9a)), 1.80-1.92
(2H, m, H-3 (H-8), H-4b (H-9b)), 2.07 (1H, m, ArCHdCHCH2a (H-
9′′a)), 2.28 (1H, m, ArCHdCHCH2b (H-9′′b)), 2.42 (1H, s, OH), 2.45
(1H, m, 5-H (H-8′)), 3.64 (1H, dd, J ) 9.1, 1.9 Hz, H-6a (H-9′a)),
3.86-3.92 (1H, overlapped, H-6b (H-9′b)), 3.856 (6H, s, OCH3), 3.861
(3H, s, OCH3), 3.87 (3H, s, OCH3), 3.88 (3H, s, OCH3), 3.92 (3H, s,
OCH3), 3.99 (1H, d, J ) 10.1 Hz, H-2, (H-7)), 5.11 (1H, d, J ) 8.5
Hz, ArCHOH (H-7′)), 5.87 (1H, m, ArCHdCHCH2 (H-8′′)), 6.19 (1H,
d, J ) 15.7 Hz, ArCHdCHCH2 (H-7′′)), 6.79-6.83 (2H, m, ArH),
6.88 (1H, d, J ) 8.2 Hz, ArH), 6.92-6.97 (3H, m, ArH); 13C NMR
(CDCl3) δ 30.0, 36.0, 37.7, 41.5, 55.75, 55.82, 55.87, 55.90, 70.3, 74.8,
86.1, 108.5, 109.2, 110.7, 110.8, 111.1, 118.8, 119.1, 120.0, 125.6,
130.7, 131.2, 133.5, 136.0, 148.3, 148.5, 148.87, 148.94, 149.0, 149.1;
HREIMS m/z 564.2726 (C25H32O6 requires, 564.2724).
Acknowledgment. We thank the president of Ehime University for
supporting this project. The 400 MHz NMR data were measured at
INCS, Ehime University. We thank the staff at this Center for the MS
measurements. We are also grateful to Marutomo Co., Iyo, Ehime,
Japan.
References and Notes
(1) Su, B.-N.; Takaishi, Y. Chem. Lett. 1999, 1315-1316.
(2) Su, B.-N.; Takaishi, Y.; Kusumi, T. Tetrahedron 1999, 55, 14571-
14586.
(3) MacRae, W. D.; Towers, G. H. N. Tetrahedron 1984, 23, 1207-
1220.
(2S,3S,5R)-5-[(S)-(Hydroxy)(3,4-dimethoxyphenyl)methyl]-3-(3,4-
dimethoxycinnamyl)-2-(3,4-dimethoxyphenyl)tetrahydropyran [(-)-
7′,8′-erythro-morinol A] (31): colorless oil; [R]20D -28 (c 0.3, CHCl3);
1H NMR (CDCl3) δ 0.87 (1H, m, H-4a (H-9a)), 1.78-1.88 (2H, m,
H-3 (H-8), H-4b (H-9b)), 2.03 (1H, m, ArCHdCHCH2a (H-9′′a)), 2.05
(1H, m, H-5 (H-8′)), 2.38 (1H, m, ArCHdCHCH2b (H-9′′b)), 3.28 (1H,
dd, J ) 11.4, 11.4 Hz, H-6a (H-9′a)), 3.84-3.89 (2H, overlapped, H-2,
H-6b (H-9′b)), 3.85 (3H, s, OCH3), 3.86 (3H, s, OCH3), 3.864 (3H, s,
OCH3), 3.870 (3H, s, OCH3), 3.88 (6H, s, OCH3), 4.38 (1H, d, J ) 7.3
Hz, ArCHOH (H-7′)), 5.85 (1H, m, ArCHdCHCH2 (H-8′′)), 6.17 (1H,
d, J ) 15.7 Hz, ArCHdCHCH2 (H-7′′)), 6.77-6.89 (9H, m, ArH);
13C NMR (CDCl3) δ 32.7, 35.9, 41.8, 43.6, 70.7, 76.1, 85.6, 108.6,
(4) Ayres, D. C.; Loike, J. D. Lignans; Cambridge University Press, 1990.
(5) Ralph, J.; Peng, J.; Lu, F.; Hatfield, R. D.; Helm, R. F. J Agric.
Food Chem. 1999, 47, 2991-2996.
(6) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75-96.
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(9) Cesati, R. R., III; Armas, J.; Hoveyda, A. H. J. Am. Chem. Soc. 2004,
126, 96-101.
(10) Yamauchi, S.; Uno, H. Org. Biomol. Chem. 2003, 1, 1323-1329.
NP060461J