Bioinspired asymmetric synthesis of (-)-gymnothelignan v

Article abstract of DOI:10.1021/acs.joc.8b00164

A bioinspired asymmetric total synthesis of a structurally unique subtype of lignan, namely, (-)-gymnothelignan V, was achieved. The key synthetic sequences involved reduction of the eupomatilone skeleton leading to (-)-gymnothelignan J followed by the fo

Full text of DOI:10.1021/acs.joc.8b00164

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Bioinspired Asymmetric Synthesis of (-)-Gymnothelignan V
Darunee Soorukram, Manat Pohmakotr, Chutima Kuhakarn, and Vichai Reutrakul
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00164 • Publication Date (Web): 02 Mar 2018
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Bioinspired Asymmetric Synthesis of
(−)-Gymnothelignan V
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Darunee Soorukram,* Manat Pohmakotr, Chutima Kuhakarn, and Vichai Reutrakul
Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCHꢀCIC),
Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
Eꢀmail: darunee.soo@mahidol.ac.th
Tel: +662 201 5148
Fax: +662 354 7151
ABSTRACT:
Bioinspired asymmetric total synthesis of structurally unique subꢀtype of lignan namely (−)ꢀ
gymnothelignan V was achieved. The key synthetic sequences involved reduction of
eupomatilone skeleton leading to (−)ꢀgymnothelignan J followed by the formation of the
corresponding oxocarbenium ion and stereoselective intramolecular FriedelꢀCrafts reaction. Our
synthetic approach provides the information to support the plausible biosynthetic pathway of this
structurally unusual lignan. On a similar basis, other structurally related natural and nonꢀnatural
gymnothelignans including (−)ꢀgymnothelignan D, 6,9ꢀbisꢀepiꢀgymnothelignan V, and 5ꢀepiꢀ
gymnothelignans D and J were readily prepared.
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Lignans are a large group of natural products derived from the dimerization of two
phenylpropanoid (C6–C3) units. The enormous structural diversity of lignans stems from various
linkage patterns between C6–C3 units, the difference of C6 groups, and a variety of relative
orientations of the substituents attaching in their molecules.1 Gymnothelignans are structurally
novel subclass of lignans bearing tetrahydrofuran (THF) ring with variable conformations and
stereochemistries across the THF ring. Gymnothelignans A−O isolated from Gymnotheca
chinensis Decne (G. chinensis), a Chinese’s traditional herbal medicine used for treatment of
contusions and strains, were reported in 2012.2 The gymnothelignans A−O could be classified to
belong to three potentially related lignan skeletons including eupomatilone3 (gymnothelignans
A−K), dibenzocyclooctadiene4 (gymnothelignans L, M, and V) and eupodienone5 skeletons
(gymnothelignans N and O) (Figure 1). Up to date, more than twentyꢀthree gymnothelignans
including gymnothelignans P−Y were isolated and identified.2,6 Despite their interesting
structural frameworks and potential biological activities, only a few syntheses of
gymnothelignans have been reported.4dꢀg,5c
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Figure 1. Structures of selected examples of gymnothelignans
(−)ꢀGymnothelignan V [(−)ꢀ1] and related derivatives bearing unique dibenzocyclooctadiene
structural framework and stereochemistries attracted our attention to develop their asymmetric
synthesis on the basis of biomimetic approach.7 Biosynthetic pathway of gymnothelignans via
spirohemiketal I was first proposed by Xu and Zhou.2a,3a An alternative biosynthetic pathway
starting from 2,5ꢀdiaryltetrahydronfuran lignans was recently proposed by She.5c Beside the
previously described biosynthetic routes, we speculated that three unique skeletons of
gymnothelignans may biogenetically be derived via spirohemiketal I derived from the
corresponding hydroxy ketone precursor3a (Scheme 1). Therefore, dehydroxylation of the
hemiketal I could give eupodienone skeleton II (gymnothelignans N and O, etc.). On the other
hand, the hemiketal I could undergo rearrangement to form eupomatilone skeleton III
(eupomatilones 1−6)3 which could further undergo reduction to provide the corresponding
gymnothelignan of types IV (gymnothelignans I and J, etc.).8 The dibenzocyclooctadiene
skeleton V [(−)ꢀ1, etc.] was proposed to be accessed by an intramolecular Friedel−Crafts reaction
through an oxocarbenium cation intermediate derived from IV. Finally, intermolecular
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nucleophilic addition through an oxocarbenium cation intermediate derived from IV should
deliver gymnothelignan of types VI (gymnothelignans A−H, and K, etc.) with diverse
substituents and contiguous stereochemistries across the THF ring. In the present work, the
synthetic conversions of III to V via IV will be described (Scheme 1).
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Scheme 1. Proposed biosynthetic pathway to gymnothelignans
Guided by the plausible biosynthetic pathway (Scheme 1), the synthetic plan to access (−)ꢀ1 was
proposed as depicted in Scheme 2. The dibenzocyclooctadiene skeleton of (−)ꢀ1 was planned to
be constructed via the intramolecular Friedel−Crafts reaction of an oxocarbenium cation
intermediate 29 which should be readily generated from (−)ꢀgymnothelignan J [(−)ꢀ3] upon
treatment with an acid. Lignan 3 should be obtained via a stereoselective reduction of
eupomatilone scaffold4 which in turn should be readily synthesized from (3S,4R,5R)ꢀγꢀ
butyrolactone 5 by halogenation reaction followed by crossꢀcoupling reaction.
Scheme 2. Synthetic plan to (−)-gymnothelignan V [(−)-1]
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The stereoselective construction of eupomatilone scaffold 4 was accomplished in a
straightforward manner starting from (3S,4R,5R)ꢀ5.3f,3i,7 Thus, iodination of (3S,4R,5R)ꢀ5 (single
isomer) using molecular iodine and silver trifluoroacetate (AgOCOCF3) in CHCl3 was readily
completed within 10 min (TLC analysis) providing 6 in 95% yield (Scheme 3). The Suzukiꢀ
Miyaura coupling3f,10 of 6 with [4ꢀ(benzyloxy)ꢀ3,5ꢀdimethoxyphenyl]boronic acid using
Pd(PPh3)4 as a catalyst in the presence of NaHCO3 in a mixture of DME and H2O as the solvents
at refluxing temperature for 15 h gave the corresponding eupomatilone product 411 which proved
to be difficult to be isolated from aromatic byꢀproducts. Fortunately, partial separation could be
achieved providing 4 in 49% yield upon careful purification of the crude mixture of 4 on silica
gel. In a straightforward synthesis, the crude mixture of 4 (dr = 9 : 1), without purification, was
subsequently subjected to debenzylation (H2, Pd/C, EtOH, rt, 20 min.) to yield the corresponding
product 7 (78% yield, dr = 9 :1, from 6). The reduction of a keto group of 7 using DIBALH in
CH2Cl2 at −78 °C for 1.5 h provided lignan 3 as a mixture of two diastereomers (45% yield, dr =
8 : 2). It is believed that the reduction reaction should proceed with high diastereoselectivity
from the less hindered face of the carbonyl moiety of 7. Isomerization could be originated from
the equilibration of the ringꢀopening and ringꢀclosing of the lactol moiety of 3. Although (−)ꢀ3
could be partially separated and fully characterized (see the Supporting Information), in the
synthetic point of view, both diastereomers of 3 yielded the same oxocarbenium cation. Thus,
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upon treatment of 3 (dr = 8 : 2) with a catalytic amount of pꢀTsOH in CH2Cl2 at room
temperature, a complete consumption of 3 was observed (TLC monitoring) after 3 h. The
corresponding oxocarbenium cation derived from 3 readily underwent stereoselective
intramolecular FriedelꢀCrafts cyclization with highly oxygenated biphenyl moiety to give the
desired product (−)ꢀ1 together with its isomer, 7ꢀepiꢀ1,12 as an inseparable mixture in 90% yield
(dr = 9 : 1). The formation of 7ꢀepiꢀ1 was proposed to proceed through the lactol ringꢀopening
under acidic conditions followed by epimerization at the α carbon of the resulting aldehyde A to
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form B leading to 7ꢀepiꢀ1 as depicted in Scheme 3. Gratifyingly, the overall yield of (−)ꢀ1 can be
improved by the followings; a phenolic moiety of 7 was protected as a silyl ether followed by the
reduction of keto group (DIBALH, CH2Cl2, −78 °C, 1.5 h) providing a diastereomeric mixture of
8 in 85% yield (dr = 8 : 2) (from 7). Without purification, intramolecular FriedelꢀCrafts
cyclization of 8 gave a mixture of 9 and 7ꢀepiꢀ9 in 93% yield (dr = 8 : 2). Upon careful
chromatographic purification (SiO2), analytical pure 9 could be separated in 69% yield. Finally,
desilylation of 9 with TBAF gave (−)ꢀ1 in 90% yield. The relative stereochemistry of (−)ꢀ1 was
confirmed on the basis of NOESY experiments. The spectroscopic characteristics of (−)ꢀ1 and
(−)ꢀ3 are in good agreement with those reported in the literature (see the Supporting
Information).
Scheme 3. Synthesis of (−)-gymnothelignan V [(−)-1] and (−)-gymnothelignan J [(−)-3]
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In order to demonstrate the viability of our biomimetic approach to access structurally complex
lignans, eupomatilone derivative 11 bearing allꢀsyn stereochemistries was synthesized from γꢀ
butyrolactone (3S,4R,5S)ꢀ10 (single isomer)3e in 64% yield (two steps). Reduction of 11 gave the
corresponding lactol which was further treated with pꢀTsOH (CH2Cl2, rt, 4 h) to promote
intramolecular FriedelꢀCrafts cyclization providing the corresponding dibenzocyclooctadiene 12
in 87% yield (dr = 8 : 2) after a twoꢀsteps reaction (Scheme 4). Debenzylation of 12 gave 6,9ꢀbisꢀ
epiꢀgymnothelignan V (13) (92% yield, dr = 8 : 2).13 Interestingly, dibenzocyclooctadiene
skeletons were found to be sensitive to acid conditions and readily underwent epimerization
under prolonged reaction time. It was found that the reaction between the lactol derived from 11
with a catalytic amount of pꢀTsOH in CH2Cl2 at room temperature for 24 h led to the formation
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of 13, 1, and 7ꢀepiꢀ1 with a ratio 1 : 2 : 1 (1H NMR analysis) after debenzylation. Since 12 (dr =
84 : 16) could be obtained when the reaction was carried out at room temperature for 4 h (TLC
monitoring), it was hypothesized that, under acidic conditions, 12 underwent ringꢀopening
reaction to form cationic intermediates C and D. Cyclization of D preferably took place to give E
with antiꢀorientation between the methyl group at Cꢀ4 and the aromatic ring at Cꢀ5 in order to
minimize the steric interaction between the two groups. Subsequent intramolecular Friedelꢀ
Crafts cyclization of E then gave 1 after debenzylation. On the other hand, epimerization at the α
carbon of D led to 7ꢀepiꢀ1 via F and G, respectively. Noteworthy, the epimerization was also
observed when 1 was treated with a catalytic amount of p-TsOH (CH2Cl2, rt, 24 h) providing a
mixture of 1, 7ꢀepiꢀ1 and 13 with a ratio 1 : 1 : 1 (1H NMR analysis).
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Scheme 4. Synthesis of 6,9-bis-epi-gymnothelignan V (13)
The synthesis of other structurally related natural and nonꢀnatural gymnothelignans, such as (−)ꢀ
gymnothelignan D [(−)ꢀ14], 5ꢀepiꢀgymnothelignan J (15), and 5ꢀepiꢀgymnothelignan D (16) was
also demonstrated (Scheme 5). Thus, treatment of 8 with a catalytic amount of pꢀTsOH in the
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presence of trimethyl orthoformate in dry MeOH at room temperature overnight (16 h) promoted
the formation of the oxocarbenium cation followed by the intermolecular nucleophilic
substitution together with desilylation providing 14 in 83% yield (dr = 71 : 16 : 13) in a single
operation. Compound (−)ꢀ14 (42% yield, dr = 9 : 1) could be separated upon careful
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chromatographic purification (SiO2). The spectroscopic characteristics of (−)ꢀ14 are in
agreement with those reported in the literature (see the Supporting Information). Similarly, 5ꢀepiꢀ
gymnothelignan J (15) and 5ꢀepiꢀgymnothelignan D (16) could be synthesized in 43% (dr = 2 :
1) and 62% yields (dr = 2 : 1), respectively. The observed diastereoselectivity for the
nucleophilic addition was proposed to occur through the attack of the nucleophile on the less
14
sterically hindered faces of favorable conformers I and K derived from 8 and 15, respectively.
The stereochemistries of 15 and 16 were established on the basis of NOESY experiments (see
the Supporting Information).
Scheme 5. Synthesis of (−)-gymnothelignan D [(−)-14], 5-epi-gymnothelignan J (15) and 5-
epi-gymnothelignan D (16)
Me
MeO
MeO
HO
Me
OMe
OMe
p-TsOH, CH(OMe)3
O
8
MeOH, rt, 16 h
42%
OMe
OMe
gymnothelignan D
)-
14
(
[( )- ] (dr = 9 : 1)
Me
HO
MeO
HO
Me
Me
MeO
MeO
HO
Me
OMe
OMe
p-TsOH, CH(OMe)3
1. H2, Pd/C, EtOH
2. DIBALH, CH2Cl2
78 oC, 1.5 h, 43%
O
O
11
OMe
MeOH, rt, 16 h
62%
OMe
OMe
OMe
OMe
OMe
5-epi-gymnothelignan D
16
5-epi-gymnothelignan J (15) (dr = 2 : 1)
(
) (dr = 2 : 1)
Nu
Me
Me
O
H
MeOH
Ar
Me
O
14
8
Me
Ar
H
I
Nu
(more favored)
Nu
Me
Ar
Ar
Me
O
O
H
MeOH
Me
16
15
Me
J
K
Nu
(more f avored)
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In conclusion, on the basis of the proposed biosynthetic pathway, we reported the first
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asymmetric total synthesis of (−)ꢀgymnothelignan V, the structurally novel
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dibenzocyclooctadiene gymnothelignan. Reduction of the eupomatilone skeleton to give (−)ꢀ
gymnothelignan J, the formation of the corresponding oxocarbenium ion followed by the
intramolecular FriedelꢀCrafts reaction were the key reactions employed. Our work provides the
information to support the plausible biosynthetic pathway of gymnothelignans which is in
accordance with She’s proposal. The viability of the synthetic approach proved to be practicable
for the synthesis of various structurally related gymnothelignans including (−)ꢀgymnothelignan
D, 6,9ꢀbisꢀepiꢀgymnothelignan V, 5ꢀepiꢀgymnothelignan J, and 5ꢀepiꢀgymnothelignan D.
Asymmetric synthesis of other members of gymnothelignans and related structures is in
progress.
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EXPERIMENTAL SECTION
General information. 1H NMR spectra were recorded on 400 or 500 MHz spectrometer and are
reported in ppm. Protonꢀdecoupled 13C NMR spectra were recorded on 75, 100, or 125 MHz
spectrometer and are reported in ppm. Reactions were monitored by thinꢀlayer chromatography
(TLC) and visualized by UV and a solution of KMnO4. Tetrahydrofuran (THF) was distilled
from sodium–benzophenone ketyl. Dichloromethane (CH2Cl2) was distilled over calcium
hydride and stored over activated molecular sieves (4 Å). Ethanol (EtOH) and methanol (MeOH)
were distilled over Mg turning. Other common solvents [CH2Cl2, hexanes, ethyl acetate
(EtOAc), MeOH, and acetone] were distilled before use. All glassware and syringes were ovenꢀ
dried and kept in a desiccator before use. Purification of the reaction products were carried out
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by column chromatography or preparative thinꢀlayer chromatography plates on silica gel.
Compounds 5 and 10 were synthesized according to the literature.3,7
7
8
9
Synthesis of compound 4: To a solution of 5 (280 mg, 1 mmol) in CHCl3 (10 mL) was added
AgOCOCF3 (221 mg, 1 mmol, 1 equiv.) in one portion under argon. Iodine (254 mg, 1 mmol, 1
equiv.) was added to the resulting suspension. The progress of the reaction was monitored by
TLC analysis. After stirring for 10 min., the reaction mixture was filtered through a Celite pad
and washed with CHCl3 (40 mL). The filtrate was washed with saturated aqueous NaHSO3 and
dried over anhydrous Na2SO4. Purification by column chromatography (30% EtOAc in hexanes)
gave compound 6 (386 mg, 95% yield). 1H NMR (400 MHz, CDCl3): δ 6.61 (s, 1H), 5.24 (d, J =
2.2 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 2.80−2.70 (m, 1H), 2.60–2.50 (m, 1H), 1.28
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1
(d, J = 7.2 Hz, 3H), 1.17 (d, J = 7.3 Hz, 3H). The H NMR data of this sample were identical
with those reported.3f A round bottom flask equipped with a magnetic stirring bar, an argon inlet,
and a reflux condenser was charged with 6 (41 mg, 0.1 mmol), [4ꢀ(benzyloxy)ꢀ3,5ꢀ
dimethoxyphenyl]boronic acid (43 mg, 0.15 mmol, 1.5 equiv.), NaHCO3 (29 mg, 0.35 mmol, 3.5
equiv.), Pd(PPh3)4 (6 mg, 5 mol%), DME (3.5 mL), and H2O (0.35 mL). The resulting mixture
was heated to reflux for 15 h. After cooling down to room temperature, the mixture was
quenched with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic
layer was washed with water and brine, and dried over anhydrous Na2SO4. Purification by
column chromatography (40% EtOAc in hexanes) gave a mixture of 4 with aromatic byꢀ
products. Careful purification by preparative thinꢀlayer chromatography (30% EtOAc in hexanes,
multiple runs) gave 4 (26 mg, 49% yield) as a pale yellow oil. [α]27D = −27 (c 0.36, CHCl3); 1H
NMR (500 MHz, CDCl3): δ 7.52−7.48 (m, 2H), 7.38−7.27 (m, 3H), 6.66 (s, 1H), 6.45 (s, 1H),
6.40 (s, 1H), 5.10 (s, 2H), 5.01 (d, J = 4.5 Hz, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.81 (s, 3H), 3.80
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(s, 3H), 3.66 (s, 3H), 2.80−2.70 (m, 1H), 2.43−2.34 (m, 1H), 1.06 (d, J = 7.5 Hz, 3H), 0.62 (d, J
5
6
13
= 7.2 Hz, 3H); C NMR (125 MHz, CDCl3): δ 179.8, 153.6, 153.5, 153.1, 151.6, 142.1, 137.7,
7
8
9
136.1, 132.5, 131.0, 128.6, 128.1, 128.0, 127.9, 108.3, 106.8, 103.8, 82.9, 74.9, 61.3, 60.9, 56.3,
56.2, 41.6, 37.1, 13.4, 9.8; IR (neat): νmax 1773, 1583, 1489, 1458, 1405, 1313, 1236, 1126, 1102
cm−1; MS: m/z (%) relative intensity 431 (M+−Bn, 100), 399 (22), 343 (24), 331 (11); HRMS
(ESIꢀTOF) calcd for C30H34O8Na [M+Na]+: 545.2151, found: 545.2150.
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Compound 7: A round bottom flask equipped with a magnetic stirring bar, an argon inlet, and a
reflux condenser was charged with 6 (36 mg, 0.09 mmol), [4ꢀ(benzyloxy)ꢀ3,5ꢀ
dimethoxyphenyl]boronic acid (39 mg, 0.14 mmol, 1.5 equiv.), NaHCO3 (28 mg, 0.3 mmol, 3.5
equiv.), Pd(PPh3)4 (6 mg, 5 mol%), DME (2 mL), and H2O (0.2 mL). The resulting mixture was
heated to reflux for 15 h. After cooling down to room temperature, the mixture was quenched
with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layer was
washed with water, brine, and dried over anhydrous Na2SO4 to give a crude mixture of 4. A
flameꢀdried round bottom flask equipped with a magnetic stirring bar, an argon inlet, and a
rubber septum was charged with the crude mixture of 4, Pd/C (10% w/w, 24 mg), and dry EtOH
(2 mL). The argon inlet was replaced by a H2 balloon, and the reaction mixture was stirred at
room temperature for 20 min. After filtration through a Celite pad, the crude mixture was
purified by column chromatography (60% EtOAc in hexanes) to yield 7 (30 mg, 78% yield)
o
(from 6) as a white solid. mp. = 136−140 C (60% EtOAc in hexanes); [α]26 = −46 (c 0.98,
D
CHCl3); 1H NMR (400 MHz, CDCl3): δ 6.65 (s, 1H), 6.47 (s, 1H), 6.43 (s, 1H), 5.63 (br s, 1H),
5.03 (d, J = 4.8 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.87 (s, 6H), 3.65 (s, 3H), 2.85−2.70 (m, 1H),
2.50−2.35 (m, 1H), 1.07 (d, J = 7.5 Hz, 3H), 0.68 (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 179.9, 153.0, 151.7, 147.0, 146.9, 142.0, 134.0, 132.6, 128.2, 126.3, 107.7, 106.2,
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103.7, 82.9, 61.2, 60.9, 56.4, 56.2, 41.6, 37.3, 13.3, 9.9; IR (neat): νmax 3442, 1762, 1598, 1460,
1404, 1104 cmꢀ1; MS: m/z (%) relative intensity 432 (M+, 63), 358 (10), 331 (100); HRMS (ESIꢀ
TOF) calcd forC23H28NaO8 [M+Na]+: 455.1682, found: 455.1698.
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(−)-Gymnothelignan J [(−)-3]: Compound 7 (44 mg, 0.1 mmol) was dissolved in dry CH2Cl2 (1
mL) and the resulting solution was cooled at −78 °C. A solution of DIBALH (1 M in hexanes)
(0.4 mL, 0.4 mmol, 5 equiv.) was added dropwise. The reaction was allowed to stir at −78 °C for
1.5 h then it was quenched with MeOH at −78 °C, allowed to warm to room temperature, and
extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with water, brine,
and dried over anhydrous Na2SO4. Purification by column chromatography (75% EtOAc in
hexanes) gave 3 (20 mg, 45% yield, dr = 81 : 19) as a pale yellow oil. (−)ꢀ(3) (8 mg, 18% yield)
could be partially separated using preparative thinꢀlayer chromatography (50% EtOAc in
hexanes, multiple runs). [α]27 = −31 (c 0.76, acetone) {lit.2a [α]20D = −4 (c 0.10, acetone)}; 1H
D
NMR (400 MHz, acetoneꢀd6): δ 7.41 (s, 1H), 6.49−6.43 (m, 2H), 5.07 (d, J = 2.0 Hz, 1H), 4.54
(d, J = 7.7 Hz, 1H), 3.85 (s, 3H), 3.81 (s, 9H), 3.58 (s, 3H), 2.45−2.35 (m, 1H), 2.15−2.05 (m,
1H), 0.78 (d, J = 7.3 Hz, 3H), 0.69 (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz, acetoneꢀd6): δ
153.7, 151.6, 148.2, 148.1, 142.1, 138.3, 135.8, 129.8, 127.8, 110.0, 108.4, 108.2, 104.4, 83.9,
61.3, 60.8, 56.8, 56.2, 45.0, 44.4, 12.4, 11.4; IR (neat): νmax 3398, 1599, 1519, 1489, 1100 cmꢀ1;
MS: m/z (%) relative intensity 434 (M+, 38), 416 (100); HRMS (ESIꢀTOF) calcd for C23H30O8Na
[M+Na]+: 457.1838, found: 457.1839. The spectral data of this sample were identical with those
reported.2a
(−)-Gymnothelignan V [(−)-1] and 7-epi-1: A solution mixture of 3 (dr = 81 : 19, 15 mg, 0.03
mmol) and a catalytic amount of pꢀTsOH in dry CH2Cl2 (1 mL) was allowed to stir at room
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temperature for 3 h. The progress of the reaction was monitored by TLC. After complete
consumption of 3, the reaction mixture was quenched with H2O (5 mL) and extracted with
EtOAc (3 × 10 mL). The combined organic layer was washed with brine and dried over
anhydrous Na2SO4. Purification by column chromatography (40% EtOAc in hexanes) gave a
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mixture of (−)ꢀ1 and 7ꢀepiꢀ1 (13 mg, 90% yield, dr = 9 : 1) as a yellow gum. H NMR (400
MHz, acetoneꢀd6, integrated equally for (−)ꢀ1 and 7ꢀepiꢀ1, signals of (−)ꢀ1 marked*): δ 7.69* (s,
1H), 7.55 (s, 1H), 7.48* (s, 1H), 6.70 (s, 1H), 6.68* (s, 1H), 5.50 (d, J = 6.1 Hz, 1H), 5.12* (d, J
= 1.8 Hz, 1H), 4.54* (d, J = 5.4 Hz, 1H), 4.44 (d, J = 6.1 Hz, 1H), 3.88* (s, 3H), 3.85* (s, 3H),
3.83 (s, 3H), 3.82* (s, 3H), 3.81* (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 3.47* (s, 3H), 3.42 (s, 3H),
2.45−2.35* (m, 1H), 2.35−2.20* (m, 1H), 1.11 (d, J = 6.7 Hz, 3H), 1.07* (d, J = 7.0 Hz, 3H),
1.06* (d, J = 7.0 Hz, 3H), 0.66 (d, J = 6.8 Hz, 3H). Some peaks of 7ꢀepiꢀ1 overlap with those of
(−)ꢀ1; 13C NMR (100 MHz, acetoneꢀd6, signals of (−)ꢀ1 marked*): δ 154.8*, 152.6*, 147.3*,
145.0*, 143.5*, 142.4*, 139.3*, 131.5*, 124.7*, 124.5*, 113.9, 113.5*, 108.4, 108.3*, 92.0,
91.4*, 85.8*, 83.1, 61.6*, 61.5*, 60.9*, 60.8, 57.0*, 56.7*, 54.6, 49.8*, 46.4, 43.4*, 17.6, 14.6*,
14.4*, 13.1. Some peaks of 7ꢀepiꢀ1 overlap with those of (−)ꢀ1.
Compound 8: Compound 7 (43 mg, 0.1 mmol) was dissolved in dry CH2Cl2 (2 mL) and then
imidazole (14 mg, 0.2 mmol) and a solution of TBSCl (30 mg, 0.2 mmol) in dry hexanes (0.5
mL) were added. The reaction mixture was allowed to stir at room temperature overnight and
then quenched with a saturated aqueous NaHCO3 solution (10 mL). The organic phase was
collected, and the aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The combined organic
phase was washed with brine and dried over anhydrous Na2SO4. Purification by column
chromatography (30% EtOAc in hexanes) gave the corresponding silylated product of 7 (52 mg,
96% yield) as a white solid. mp. = 88−90 C (30% EtOAc in hexanes); [α]25 = −36 (c 0.32,
o
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CHCl3); H NMR (400 MHz, CDCl3): δ 6.65 (s, 1H), 6.43 (br s, 1H), 6.39 (d, J = 1.1 Hz, 1H),
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5.08 (d, J = 4.2 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.78 (s, 6H), 3.61 (s, 3H), 2.80−2.70 (m, 1H),
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2.45−2.35 (m, 1H), 1.05 (d, J = 7.5 Hz, 3H), 1.20 (s, 9H), 0.66 (d, J = 7.1 Hz, 3H), 0.15 (s, 6H);
13C NMR (100 MHz, CDCl3): δ 180.0, 152.9, 151.7, 151.6, 151.5, 142.0, 133.7, 132.7, 128.3,
127.7, 108.2, 106.6, 103.6, 83.0, 61.2, 60.9, 56.2, 55.9, 55.8, 41.6, 37.1, 29.7, 25.8, 13.5, 9.7,
−4.7; IR (neat): νmax 1779, 1582, 1456, 1404, 1314, 1259 cmꢀ1; MS: m/z (%) relative intensity
547 (M+, 1), 489 (100); HRMS (ESIꢀTOF) calcd for C29H42O8SiNa [M+Na]+: 569.2547, found:
569.2548. The obtained silylated product of 7 (37 mg, 0.07 mmol) was dissolved in dry CH2Cl2
(1 mL) under an argon atmosphere, and the resulting solution was cooled at −78 °C. A solution
of DIBALH (1 M in hexanes) (0.14 mL, 0.14 mmol, 2 equiv.) was added dropwise. After stirring
at −78 °C for 1.5 h, the reaction mixture was quenched with MeOH (2 mL) at −78 °C, allowed to
warm to room temperature, and extracted with EtOAc (3 × 10 mL). The combined organic layer
was washed with brine and dried over anhydrous Na2SO4. Purification by column
chromatography (40% EtOAc in hexanes) gave 8 (33 mg, 89% yield) as a mixture of
diastereomers (83 : 17). The crude mixture of 8 was further used in the next step without
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purification. H NMR (400 MHz, acetoneꢀd6): δ 7.41 (s, 1H), 6.50−6.40 (m, 2H), 5.45−5.35 (m,
1H), 5.12−5.06 (m, 1H), 4.53 (d, J = 7.4 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 3.79 (s,
3H), 3.59 (s, 3H), 2.43−2.33 (m, 1H), 2.15−2.05 (m, 1H), 1.03 (s, 9H), 0.79 (d, J = 7.3 Hz, 3H),
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0.69 (d, J = 7.1 Hz, 3H), 0.15 (s, 3H), 0.13 (s, 3H); C NMR (100 MHz, acetoneꢀd6): δ 153.8,
152.0, 151.9, 151.6, 142.1, 138.3, 133.9, 130.2, 129.7, 109.6, 108.2, 107.9, 104.6, 84.0, 61.3,
60.8, 56.3, 56.2, 44.9, 44.4, 26.3, 19.4, 12.6, 11.3, 1.5, −4.3; HRMS (ESIꢀTOF) calcd for
C29H44O8SiNa [M+Na]+: 571.2703, found: 571.2706.
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(−)-Gymnothelignan V [(−)-1]: A solution mixture of 8 (15 mg, 0.03 mmol) and a catalytic
amount of pꢀTsOH in dry CH2Cl2 (1 mL) was allowed to stir at room temperature for 6 h. The
progress of the reaction was monitored by TLC analysis. Then, the reaction mixture was
quenched with H2O (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layer
was washed with brine and dried over anhydrous Na2SO4 to provide a mixture of 9 and 7ꢀepiꢀ9
(13.5 mg, 93% yield, dr = 8 : 2). Careful purification of the mixture of 9 and 7ꢀepiꢀ9 using
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preparative thinꢀlayer chromatography on silica gel (20% EtOAc in hexanes, multiple runs)
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provided 9 in 69% yield (10 mg). [α]26 = −8.6 (c 0.45, CH2Cl2); H NMR (400 MHz, acetoneꢀ
D
d6): δ 7.50 (s, 1H), 6.69 (s, 1H), 5.11 (d, J = 1.9 Hz, 1H), 4.57 (d, J = 5.0 Hz, 1H), 3.87 (s, 3H),
3.82 (s, 6H), 3.81 (s, 3H), 3.48 (s, 3H), 2.43−2.33 (m, 1H), 2.33−2.23 (m, 1H), 1.08 (d, J = 2.2
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Hz, 3H), 1.06 (d, J = 2.3 Hz, 3H), 1.04 (s, 9H), 0.19 (s, 3H), 0.17 (s, 3H). C NMR (125 MHz,
acetoneꢀd6): δ 154.5, 152.4, 150.1, 148.9, 143.1, 141.9, 137.5, 131.1, 126.6, 123.9, 113.4, 107.8,
91.0, 85.1, 61.1, 61.0, 60.7, 56.2, 55.7, 48.8, 43.6, 26.2, 19.2, 14.1, 13.9, −4.3, −4.4; HRMS
(ESIꢀTOF) calcd for C29H43O7Si [M+H]+: 553.2778, found: 531.2777.
Treatment of 9 with a solution of TBAF in THF for 1 h gave (−)ꢀ1 (7 mg, 90% yield) as a yellow
gum after purification by column chromatography (30% EtOAc in hexanes). [α]26 = −9.3 (c
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0.67, MeOH) {lit.2d [α]20 = −19 (c 0.31, MeOH)}; H NMR (400 MHz, acetoneꢀd6): δ 7.67 (s,
D
1H), 7.48 (s, 1H), 6.68 (s, 1H), 5.12 (d, J = 1.5 Hz, 1H), 4.54 (d, J = 5.3 Hz, 1H), 3.89 (s, 3H),
3.86 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.49 (s, 3H), 2.43−2.33 (m, 1H), 2.33−2.25 (m, 1H), 1.07
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(d, J = 7.0 Hz, 3H), 1.06 (d, J = 7.0 Hz, 3H); C NMR (100 MHz, acetoneꢀd6): δ 154.3, 152.1,
146.8, 144.5, 143.0, 141.9, 138.8, 131.0, 124.2, 124.1, 113.0, 107.8, 90.9, 85.2, 61.1, 61.0, 60.4,
56.5, 56.2, 49.3, 42.9, 14.1, 13.9; IR (neat): νmax 3364, 1593, 1447, 1296, 1098 cmꢀ1; MS: m/z
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(%) relative intensity 416 (M+, 100), 371 (10), 358 (23); HRMS (ESIꢀTOF) calcd for
C23H28O7Na [M+Na]+: 439.1733, found: 439.1732.
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The spectral data of this sample were identical with those reported.2d
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Compound 11: According to the procedure for the synthesis of 4, iodination of 10 (56 mg, 0.2
mmol) using I2 (52 mg, 0.2 mmol, 1 equiv.) and AgOCOCF3 (45 mg, 0.2 mmol, 1 equiv.) in
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CHCl3 (3 mL) gave the corresponding aryl iodide (72 mg, 89% yield). H NMR (400 MHz,
CDCl3): δ 6.79 (s, 1H), 5.55 (d, J = 5.0 Hz, 1H), 3.88 (s, 6H), 3.87 (s, 3H), 3.35−3.25 (m, 1H),
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3.10–3.00 (m, 1H), 1.21 (d, J = 7.2 Hz, 3H), 0.49 (d, J = 7.3 Hz, 3H). The H NMR data of this
sample were identical with those reported.3f Crossꢀcoupling reaction of the obtained aryl iodide
(35 mg, 0.08 mmol) using [4ꢀ(benzyloxy)ꢀ3,5ꢀdimethoxyphenyl]boronic acid (39 mg, 0.13
mmol), NaHCO3 (27 mg, 0.32 mmol), Pd(PPh3)4 (7 mg, 5 mol%), DME (3.5 mL), and H2O (0.35
mL) gave 11 (32.5 mg, 72% yield) after purification by column chromatography (30% EtOAc in
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hexanes). [α]31 = −27 (c 0.31, CHCl3); H NMR (400 MHz, CDCl3): δ 7.54−7.46 (m, 2H),
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7.40−7.25 (m, 3H), 6.83 (s, 1H), 6.42 (d, J = 2.2 Hz, 1H), 6.31 (d, J = 2.2 Hz, 1H), 5.33 (d, J =
6.5 Hz, 1H), 5.11 (s, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.67 (s, 3H),
13
2.73−2.60 (m, 1H), 2.13−2.00 (m, 1H), 1.11 (d, J = 9.6 Hz, 3H), 0.53 (d, J = 9.8 Hz, 3H); C
NMR (75 MHz, CDCl3): δ 178.7, 153.6, 153.4, 152.9, 151.2, 141.6, 137.7, 135.9, 131.2, 129.9,
128.5, 128.0, 127.8, 126.7, 107.6, 106.1, 104.9, 80.4, 74.8, 61.3, 60.9, 56.3, 40.7, 38.8, 9.9, 9.7;
IR (neat): νmax 1776, 1582, 1126, 1104 cm−1; MS: m/z (%) relative intensity 522 (M+, 36), 431
(100); HRMS (ESIꢀTOF) calcd for C30H34NaO8 [M + Na]+: 545.2151, found: 545.2152.
Compound 12: Compound 11 (25 mg, 0.05 mmol) was dissolved in dry CH2Cl2 (1 mL) and the
resulting solution was cooled at −78 °C. A solution of DIBALH (1 M in hexanes) (0.1 mL, 0.1
mmol, 2 equiv.) was added dropwise. The reaction was allowed to stir at −78 °C for 1.5 h then it
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was quenched with MeOH at −78 °C, allowed to warm to room temperature, and extracted with
EtOAc (3 × 10 mL). The combined organic layer was washed with brine, and dried over
anhydrous Na2SO4. The obtained crude mixture was dissolved in dry CH2Cl2 (1 mL) and a
catalytic amount of pꢀTsOH was added. The reaction mixture was allowed to stir at room
temperature for 4 h, quenched with H2O (5 mL) and extracted with EtOAc (3 × 10 mL). The
combined organic layer was washed with brine and dried over anhydrous Na2SO4. Purification
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by column chromatography (30% EtOAc in hexanes) gave 12 (21 mg, 87% yield, after two
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steps) as a pale yellow oil. [α]25 = +0.3 (c 0.68, CHCl3); H NMR (400 MHz, acetoneꢀd6): δ
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(s, 2H), 5.05 (d, J = 6.2 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.47 (s,
3H), 2.16−2.08 (m, 1H), 1.88−1.78 (m, 1H), 1.18 (d, J = 6.7 Hz, 3H), 0.58 (d, J = 6.9 Hz, 3H);
13C NMR (100 MHz, acetoneꢀd6): δ 154.5, 152.5, 152.2, 150.8, 143.0, 140.3, 139.3, 135.1,
132.8, 129.5, 129.1, 128.9, 128.6, 124.9, 115.4, 108.2, 88.2, 82.2, 75.4, 62.4, 61.5, 61.2, 56.6,
56.3, 53.7, 46.2, 17.6, 13.9; IR (neat): νmax 1264, 1128, 1100 cm−1; MS: m/z (%) relative
intensity 506 (M+, 40), 415 (100); HRMS (ESIꢀTOF) calcd for C30H35O7 [M + H]+: 507.2383,
found: 507.2381.
6,9-Bis-epi-gymnothelignan V (13): Debenzylation of 12 (15 mg, 0.03 mmol) using H2 balloon,
Pd/C (10% w/w, 3 mg), and dry EtOH (1 mL) for 20 min and filtration through a Celite pad
followed by purification by column chromatography (60% EtOAc in hexanes) gave 13 (11 mg,
92% yield) as a pale yellow oil. [α]25D = +0.5 (c 0.62, EtOAc); 1H NMR (400 MHz, acetoneꢀd6):
δ 7.64 (s, 1H), 7.47 (s, 1H), 6.50 (s, 1H), 5.11 (d, J = 5.8 Hz, 1H), 5.03 (d, J = 6.2 Hz, 1H), 3.86
(s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.46 (s, 3H), 2.15−2.05 (m, 1H), 1.90−1.80 (m,
1H), 1.18 (d, J = 6.7 Hz, 3H), 0.57 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, acetoneꢀd6): δ
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154.2, 152.0, 147.0, 145.0, 142.9, 138.7, 134.7, 132.9, 125.3, 124.3, 114.5, 108.2, 88.3, 82.2,
61.5, 61.4, 61.2, 56.8, 56.3, 53.6, 46.3, 17.7, 13.9; IR (neat): νmax 3378, 1596, 1490, 1463, 1260
cmꢀ1; MS: m/z (%) relative intensity 416 (M+, 100), 347 (29); HRMS (ESIꢀTOF) calcd for
C23H28NaO7 [M + Na]+: 439.1733, found: 439.1732.
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(−)-Gymnothelignan D [(−)-14]: A solution of 8 (15 mg, 0.03 mmol) in dry MeOH (1.5 mL)
and CH(OMe)3 (0.1 mL) was treated with pꢀTsOH (cat.). After stirring at room temperature
overnight (16 h), the reaction mixture was quenched with H2O (5 mL) and extracted with EtOAc
(3 × 10 mL). The combined organic layer was washed with brine and dried over anhydrous
Na2SO4. Purification by column chromatography (25% CH2Cl2:25% EtOAc in hexanes) gave a
diastereomeric mixture of 14 (10 mg, 83% yield, dr = 71 : 16 : 13) as pale yellow oil. Careful
chromatographic purification using preparative thinꢀlayer chromatography on silica gel (20%
EtOAc in hexanes, multiple runs) provided (−)ꢀ14 in 42% yield (5 mg). [α]26 = −14.5 (c 0.87,
D
1
CHCl3) {lit.2a [α]20 = −12 (c 0.03, MeOH)}; H NMR (400 MHz, acetoneꢀd6): δ 7.22 (s, 1H),
D
7.09 (s, 1H), 6.45 (br s, 2H), 4.59 (s, 1H), 4.58 (d, J = 8.5 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H),
3.82 (s, 3H), 3.81 (s, 3H), 3.59 (s, 3H), 3.44 (s, 3H), 2.46−2.35 (m, 1H), 2.22−2.12 (m, 1H), 0.78
13
(d, J = 7.3 Hz, 3H), 0.74 (d, J = 7.0 Hz, 3H); C NMR (125 MHz, acetoneꢀd6): δ 153.9, 151.7,
148.3, 148.2, 142.3, 137.5, 136.0, 130.3, 127.6, 111.7, 110.1, 108.5, 107.6, 84.2, 61.2, 60.8, 56.8,
56.7, 56.1, 55.1, 44.5, 44.2, 11.9, 11.3; IR (neat): νmax 3414, 1600, 1490, 1461, 1099 cmꢀ1; MS:
m/z (%) relative intensity 448 (M+, 74), 376 (100); HRMS (ESIꢀTOF) calcd for C24H32O8Na
[M+Na]+: 471.1995, found: 471.1999. The spectral data of this sample were identical with those
reported.2a
5-epi-Gymnothelignan J (15): Debenzylation of 11 (17 mg, 0.03 mmol) using H2 balloon, Pd/C
(10% w/w, 3 mg), and dry EtOH (1 mL) for 20 min followed by reduction of the resulting
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product using DIBALH (1 M in hexanes) (0.1 mL, 0.1 mmol, 2 equiv.) gave 15 (6 mg, 43%
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yield, dr = 2 : 1) as pale yellow oil. H NMR (400 MHz, acetoneꢀd6, integrated equally for both
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diastereomers, major isomer marked*): δ 7.23 (s, 1H), 7.01* (s, 1H), 6.47* (d, J = 1.2 Hz, 1H),
6.45 (d, J = 1.4 Hz, 1H), 6.38* (d, J = 1.2 Hz, 1H), 6.37 (d, J = 1.4 Hz, 1H), 5.25 (d, J = 5.2 Hz,
1H), 5.15* (d, J = 4.5 Hz, 1H), 5.11* (d, J = 5.9 Hz, 1H), 4.91 (d, J = 6.1 Hz, 1H), 3.85* (s, 3H),
3.84 (s, 3H), 3.83 (s, 6H), 3.82 (s, 3H), 3.81* (s, 6H), 3.79* (s, 3H), 3.59 (s, 3H), 3.58* (s, 3H),
2.25ꢀ2.15 (m, 1H), 2.10ꢀ2.00* (m, 1H), 1.95ꢀ1.85 (m, 2H), 0.96 (d, J = 6.9 Hz, 3H), 0.94* (d, J =
7.1 Hz, 3H), 0.67 (d, J = 7.5 Hz, 3H), 0.49* (d, J = 7.4 Hz, 3H). Some peaks of minor isomer
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overlap with those of major isomer; C NMR (125 MHz, acetoneꢀd6, major isomer marked*): δ
152.3*, 152.2, 151.3*, 151.0, 141.1*, 140.9*, 135.6, 135.0, 134.2*, 127.4*, 127.3, 127.1, 126.9*,
108.3*, 108.2, 107.5, 107.0*, 106.9, 106.3*, 103.0*, 98.9, 82.2, 80.0*, 60.4*, 59.9, 55.9*, 55.8,
55.4*, 55.3, 45.7*, 42.0, 40.9*, 39.4, 11.3*, 9.4*, 9.3. Some peaks of minor isomer overlap with
those of major isomer; IR (neat): νmax 3416, 1720, 1599, 1489, 1099 cmꢀ1; MS: m/z (%) relative
intensity 434 (M+, 37), 416 (100); HRMS (ESIꢀTOF) calcd for C23H30O8Na [M+Na]+: 457.1838,
found: 457.1833.
5-epi-Gymnothelignan D (16): A solution of 15 (14 mg, 0.03 mmol) in dry MeOH (1 mL) and
CH(OMe)3 (0.1 mL) was treated with pꢀTsOH (cat.). After stirring at room temperature
overnight (16 h), the reaction mixture was quenched with H2O (5 mL) and extracted with EtOAc
(3 × 10 mL). The combined organic layer was washed with brine and dried over anhydrous
Na2SO4. Purification by column chromatography (25% CH2Cl2:25% EtOAc in hexanes) gave 16
1
(9 mg, 62% yield, dr = 2 : 1) as pale yellow oil. H NMR (400 MHz, CDCl3, integrated equally
for both diastereomers, major isomer marked*): δ 6.97* (s, 2H), 6.45* (s, 2H), 6.31* (s, 2H),
5.54* (s, 2H), 5.08* (d, J = 4.6 Hz, 1H), 4.98 (d, J = 6.2 Hz, 1H), 4.78 (d, J = 5.3 Hz, 1H), 4.71*
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(d, J = 5.2 Hz, 1H), 3.93* (s, 3H), 3.92 (s, 3H), 3.90 (s, 3H), 3.89* (s, 6H), 3.88 (s, 3H), 3.86* (s,
3H), 3.85* (s, 3H), 3.65 (s, 3H), 3.64* (s, 3H), 3.52 (s, 3H), 3.42* (s, 3H), 2.30ꢀ2.20 (m, 1H),
2.20ꢀ2.10* (m, 1H), 1.95ꢀ1.80* (m, 2H), 0.98* (d, J = 7.2 Hz, 3H), 0.95 (d, J = 7.2 Hz, 3H), 0.63
(d, J = 7.5 Hz, 3H), 0.50* (d, J = 7.4 Hz, 3H); Some peaks of minor isomer overlap with those of
major isomer; 13C NMR (125 MHz, CDCl3, major isomer marked*): δ 152.3, 151.2*, 146.8*,
146.6*, 140.9*, 140.7, 133.7*, 133.6, 133.5*, 127.6, 127.4*, 127.2*, 110.4*, 107.2*, 107.1,
106.7, 106.4, 106.0*, 106.0, 105.8*, 82.8, 80.5*, 61.3, 61.2*, 60.9*, 56.4, 56.3, 56.2*, 56.1*,
55.7*, 55.6, 44.1*, 41.9, 40.3*, 39.2, 12.3*, 11.8, 10.1*, 9.5. Some peaks of minor isomer
overlap with those of major isomer; IR (neat): νmax 3402, 1599, 1459, 1099 cmꢀ1; MS: m/z (%)
relative intensity 448 (M+, 60), 376 (100); HRMS (ESIꢀTOF) calcd for C24H32NaO8 [M+Na]+:
471.1995, found: 471.2016.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Copies of 1H and 13C NMR spectra of characterized compounds, NOESY spectra of compounds
4, (−)ꢀ1, 11, 12, 13, 14, 15, and 16
AUTHOR INFORMATION
Corresponding Author
*Tel: (+)ꢀ66ꢀ2ꢀ2015148. Fax: (+)ꢀ66ꢀ2ꢀ3547151. Eꢀmail: darunee.soo@mahidol.ac.th
ACKNOWLEDGMENT
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We would like to thank the Thailand Research Fund (RSA5880013 and IRN58W0005), the
Center of Excellence for Innovation in Chemistry (PERCHꢀCIC), the Office of the Higher
Education Commission and Mahidol University under the National Research Universities
Initiative, Mahidol University, Swedish Research Council through Swedish Research Links
Programme (2013ꢀ6744), CNRSꢀPICS Program (PICS 6663) and The FrancoꢀThai Cooperation
Program in Higher Education and Research (PHCꢀSiam 2017) for financial support.
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REFERENCES
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Tetrahedron Lett. 2011, 52, 581. (h) Hirokawa, Y.; Kitamura, M.; Mizubayashi, M.; Nakatsuka,
R.; Kobori, Y.; Kato, C.; Kurata, Y.; Maezaki, N. Eur. J. Org. Chem. 2013, 721. (i) Kitamura,
M.; Hirokawa, Y.; Maezaki, N. Chem. Eur. J. 2009, 15, 9911, and references cited therein.
(4) For isolation, see, for example: (a) Luo, Y.ꢀQ.; Liu, M.; Wen, J.; Wang, W.ꢀG.; Hu, K.;
Li, X.ꢀN.; Du, X.; Pu, J.ꢀX.; Sun, H.ꢀD. Fitoterapia 2017, 119, 150. (b) Hu, D.; Han, N.; Yao,
X.; Liu, Z.; Wang, Y.; Yang, J.; Yin, J. Planta Med. 2014, 80, 671. (c) Ding, J.ꢀY.; Yuan, C.ꢀM.;
Cao, M.ꢀM.; Liu, W.ꢀW.; Yu, C.; Zhang, H.ꢀY.; Zhang, Y.; Di, Y.ꢀT.; He, H.ꢀP.; Li, S.ꢀL.; Hao,
X.ꢀJ. J. Nat. Prod. 2014, 77, 1800. For synthesis, see, for example: (d) Pelter, A.; Satchwell, P.;
Ward, R. S.; Blake, K. J. Chem. Soc., Perkin Trans. 1 1995, 18, 2201. (e) Gong, W.; RajanBabu,
T. V. Chem. Sci. 2013, 4, 3979. (f) Li, Y.; Wang, Q.; Dong, L.; Guo, X.; Wang, W.; Xie, J.;
Chang, J. Synthesis 2009, 3383. (g) Chen, P.; Huo, L.; Li, H.; Liu, L.; Yuan, Z.; Zhang, H.; Feng,
S.; Xie, X.; Wang, X.; She, X. Org. Chem. Front. 2018, DOI: 10.1039/c8qo00026c, and
references cited therein.
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(5) For isolation, see: (a) Read, R.; Taylor, W. Aust. J. Chem. 1981, 34, 1125. (b) Bowden,
B.; Read, R.; Taylor, W. Aust. J. Chem. 1981, 34, 799. See also ref. 2 and 4. For synthesis, see,
for example: (c) Li, H.; Zhang, Y.; Xie, X.; Ma, H.; Zhao, C.; Zhao, G.; She, X. Org. Lett. 2014,
16, 4440.
(6) For related structures of gymnothelignans, see, for example: (a) Xiao, S.ꢀJ.; Lei, X.ꢀX.;
Xia, B.; Xu, D.ꢀQ.; Xiao, H.ꢀP.; Xu, H.ꢀX.; Chen, F.; Ding, L.ꢀS.; Zhou, Y. Tetrahedron Lett.
2014, 55, 5949. (b) Xiao, S.ꢀJ.; Zhang, M.ꢀS.; Guo, D.ꢀL.; Chen, F.; Zhou, Y.; Ding, L.ꢀS. Chin.
Chem. Lett. 2017, 28, 1049. See also ref. 2, 4, and 5.
(7) For our works on asymmetric synthesis of lignans, see, (a) Soorukram, D.; Panmuang, J.;
Tuchinda, P.; Kuhakarn, C.; Reutrakul, V.; Pohmakotr, M. Tetrahedron 2014, 70, 7577. (b)
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Yodwaree, S.; Soorukram, D.; Kuhakarn, C.; Tuchinda, P.; Reutrakul, V.; Pohmakotr, M.; Org.
Biomol. Chem. 2014, 12, 6885. (c) Chaimanee, S.; Pohmakotr, M.; Kuhakarn, C.; Reutrakul, V.;
Soorukram, D. Org. Biomol. Chem. 2017, 15, 3985. (d) Pohmakotr, M.; Kuhakarn, C.;
Reutrakul, V.; Soorukram, D. Tetrahedron Lett. 2017, 58, 4740.
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(8) The relative stereochemistry between Cꢀ4 and Cꢀ5 of gymnothelignans, except
gymnothelignans C and H, was proposed to be 4,5ꢀanti stereochemistry.
(9) See, for example: (a) Solorio, D. M.; Jennings, M. P. J. Org. Chem. 2007, 72, 6621. (b)
Solorio, D. M.; Jennings, M. P. Org. Lett. 2009, 11, 189. (c) Fañanás, F. J.; Fernández, A.;
Çevic, D.; Rodríguez, F. J. Org. Chem. 2009, 74, 932. (d) Eey, S. T.ꢀC.; Lear, M. J. Org. Lett.
2010, 12, 5510. (e) Kaufman, T. S.; Larghi, E. L. Eur. J. Org. Chem. 2011, 5195. (f) Castillo, R.
R.; Aquino, M.; Gandara, Z.; Safir, I.; Elkhayat, Z.; Retailleau, P.; Arseniyadis, S. Org. Lett.
2012, 14, 1628. (g) Ghosh, A. K.; Martyr, C. D.; Xu, C.ꢀX. Org. Lett. 2012, 14, 2002. (h) Meng,
F.; Jang, H.; Hoveyda, A. H. Chem. Eur. J. 2013, 19, 3204. (i) Albury, A. M. M.; De Joarder, D.;
Jennings, M. P. Tetrahedron Lett. 2015, 56, 3057. See also, ref. 4g.
(10) For SuzukiꢀMiyaura coupling reaction; see, for example: (a) Chatterjee, A.; Ward, T. R.
Catal. Lett. 2016, 146, 820. (b) Hussain, I.; Capricho, J.; Yawer, M. A. Adv. Synth. Catal. 2016,
358, 3320. (c) Polshettiwar, V.; Decottignies, A.; Len, C.; Fihri, A. ChemSusChem. 2010, 3, 502.
(11) Compound 4 was obtained along with its diastereomer (dr = 9 : 1) after SuzukiꢀMiyaura
coupling. See, also ref. 3e for the epimerization of the γꢀbutyrolactones during SuzukiꢀMiyaura
coupling reaction.
(12) The stereochemistries of 7ꢀepiꢀ1 were assigned based on the comparison of the coupling
constants between protons Hꢀ6/Hꢀ7 (3J = 6.1 Hz) and Hꢀ8/Hꢀ9 (3J = 6.1 Hz) of 7ꢀepiꢀ1 with those
of related structure, gymnothelignan M. See ref. 2a.
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(13) The observed variation of coupling constants between protons Hꢀ6/Hꢀ7 and Hꢀ8/Hꢀ9 of
compounds 1, 9, 12, and 13 is possibly the results from the HꢀCꢀCꢀH dihedral angles in a rigid
[4.1.2]ꢀbridged bicyclic system.
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(14 ) (a) Smith, D. M.; Tran, M. B.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 14149. (b)
Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am. Chem. Soc. 1999, 121, 12208.
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