Structural Elucidation and Total Synthesis of Three 9-Norlignans from Curculigo capitulata

Article abstract of DOI:10.1021/acs.joc.9b00170

Capitulactones A-C, three unprecedented 9-norlignans featuring a unique 3,5-dihydrofuro[2,3-d]oxepin-7(2H)-one scaffold, were isolated from the roots of Curculigo capitulata. Their structures with absolute configurations were unambiguously established by

Full text of DOI:10.1021/acs.joc.9b00170

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Article
Structural Elucidation and Total Synthesis of
Three 9-Norlignans from Curculigo capitulata
Song Li, Jin-Hai Yu, Yao-Yue Fan, Qun-Fang Liu, Zhan-Chao Li, Zhi-Xiang Xie, Ying Li, and Jian-min Yue
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00170 • Publication Date (Web): 20 Mar 2019
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Structural Elucidation and Total Synthesis of Three
9-Norlignans from Curculigo capitulata
Song Li,†, § Jin-Hai Yu,‡, § Yao-Yue Fan, ‡, § Qun-Fang Liu,‡ Zhan-Chao Li,† Zhi-Xiang Xie,† Ying
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Li*,† and Jian-Min Yue*,‡
†State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou 730000, People’s Republic of China
‡State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academyof Sciences, 555
Zu Chong Zhi Road, Shanghai, 201203, People’s Republic of China
Abstract:
Capitulactones
AC,
three
unprecedented
9-norlignans
featuring
a
unique
3,5-dihydrofuro[2,3-d]oxepin-7(2H)-one scaffold, were isolated from the roots of Curculigo
capitulata. Their structures with the absolute configurations were unambiguously established by a
combination of spectroscopic data, ECD analysis, and total synthesis. Biomimetic total syntheses
of three pairs of the corresponding enantiomers were achieved in 910 steps with overall yields of
14.8%, 12.7%, and 10.3%, respectively. Notably, the unique scaffold of the common western
hemisphere of the molecules was constructed by using the oxidation-reduction strategy from
benzodihydrofuran.
Introduction
The genus Curculigo (Amaryllidaceae) comprises about 20 species in the world, and some of
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which have been used as traditional medicine, and have been demonstrated to exhibit
immunostimulatory, antiosteoporotic, vasoconstrictor, antioxidant, antihistaminic, and
antiasthmatic activities.1,2 The plant of Curculigo capitulata (Lour.) O. Ktze. (Hypoxidaceae) is a
herb and widely distributed in the Southern China,1 and has long been applied in the remedy of
traditional Chinese medicine for the treatment of many diseases, such as consumptive cough,
kidney asthenia, impotence, and asthma.2 The previous chemical investigation on the Curculigo
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species led to the isolation of a number of norlignans, triterpenoids, and other phenolics.3 10

Among them, sinenside A, a novel norlignan glucoside isolated form C. sinensis,3 has been
synthesized.11 In our current study, three unprecedented 9-norlignans, named capitulactones AC
(13) (Figure 1) featuring a unique 3,5-dihydrofuro[2,3-d]oxepin-7(2H)-one motif were isolated
from the roots of Curculigo capitulata. The structures of these compounds were elucidated based
on spectroscopic data analysis, and their absolute stereochemistry was determined by total
synthesis. To determine the stereochemistry of compounds 13, a synthetic strategy involving a
oxidation-reduction reaction method as the key step was implemented, which allowed the
unambiguous assignment of their absolute configuration. Herein, we report the isolation and
structural elucidation of the three natural products and the total syntheses of three pairs of the
corresponding enantiomers.
Figure 1. Structures of compounds 13.
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Results and Discussion
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Capitulactone A (1) was obtained as an amorphous powder and displayed an ion peak at m/z
283.0964 [M  H] (calcd 283.0976) in the ()-HRESIMS spectrum, which together with the 13C
NMR data assigned a molecular formula of C17H16O4 for 1, with 10 indices of hydrogen
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1
deficiency. In the H NMR spectrum, two inter-coupled doublets observed at H 6.82 and 7.13
(each 2H, d, J = 8.5 Hz) suggested the presence of a para-disubstituted phenyl group, and the
other set of inter-coupled signals resonated at H 6.55 and 5.54 with the coupling constant of J =
11.6 Hz revealed the existence of a cis-double bond functionality. The 13C NMR data (Table S1,
see Supporting Information) displayed 17 carbon resonances, which were classified with the aid of
DEPT and HSQC spectra into three methylenes (one oxygenated), nine methines (eight olefinic
and one oxygenated), and five quaternary carbons (one ester carbonyl and four olefinic). Except
for the aforementioned phenyl group and a cis-double bond, the remaining four olefinic carbons
revealed the presence of another two double bonds in compound 1. Additionally, the
above-mentioned functionalities occupied eight out of 10 indices of hydrogen deficiency, and the
remaining two required two additional rings in the skeleton of 1. Comprehensive analyses of the
2D NMR spectra (Figure 2) allowed the establishment of the planar structure of compound 1. In
1
detail, analysis of the H1H COSY data unambiguously outlined four spin coupling systems [a
(C-5 to C-6), b (C-7 to C-7 via C-8, C-9, and C-8 in sequence), c (C-2 to C-3), and d (C-5 to
C-6), Figure 2]. Fragments c and d along with the key HMBC correlations of H-2 and H-6/C-4
(C 154.8) and H-3 and H-5/C-1 (C 129.4) further corroborated the presence of a
para-disubstituted phenyl group, which was then connected to fragment b via a carbon-carbon
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bond (C-1‒C-7) as confirmed by the key HMBC correlations from H-7 to C-1, C-2 (C 130.1),
and C-3 (C 115.3). In addition, a hydroxy group was attached at C-4, which was deduced by the
downfield-shifted carbon resonance of C-4 and the HMBC correlations from OH-4 to C-3, C-5,
and C-4. Subsequently, a 3,5-dihydrofuro[2,3-d]oxepin-7(2H)-one motif was constructed by the
corresponding NMR data, the spin coupling systems of H-5/H-6 and H-7/H-8, combined with the
HMBC correlations of H-3/ C-1, C-2, and C-4 (C 169.4); H2-5/ C-1 and C-4; H-6/C-1, C-2, and
C-7 (C 35.6); and H2-7 and H-8/C-1 (C 140.6) and C-2 (C 166.4). Thus, compound 1 was
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determined
as
an
unprecedented
9-norlignan
featuring
a
unique
3,5-dihydrofuro[2,3-d]oxepin-7(2H)-one moiety, which was the first report in the lignan family.
The absolute configuration of the only stereocenter (C-8) in 1 was determined by the exciton
chirality method (ECM), which is one of the most popular approaches to assign the absolute
configuration of organic molecules, and especially natural products.12 In the ECD spectrum of 1
(Figure 3A), the positive Cotton effect at λmax = 237 nm (Δε 0.7) and the negative Cotton effect at
λmax = 297 nm (Δε – 0.7) indicated a negative chirality for 1, which is resulted from the exciton
coupling of two different chromophores of the styrene moiety and the enone group in
7(2H)-oxepinone ring.13 The positive chirality and counter-clockwise arrangement of the electric
transition dipole of two chromophores (Figure 3B) allowed the assignment of the absolute
configuration of capitulactone A as 8S.
Figure 2. 1H1H COSY and key HMBC correlations for compound 1.
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Figure 3. (A) CD curves for compounds 13; (B) arrow denotes the electric transition dipole
of two chromophores of compound 1.
Compound 2 had a molecular formula of C18H18O4 as inferred from its ()-HRESIMS ion peak
1
at m/z 619.2326 [2M + Na]+ (calcd 619.2302) and the 13C NMR data. Comparison of the H and
13C NMR data (Table S1) with those of 1 revealed that they were structural analogues with the
main difference occurring at the phenyl group, where the carbon resonance of C-3 (C-5) was
upfield shifted by C 1.5 ppm and that of C-4 was downfield shifted by C 3.9 ppm. Such
variation in chemical shifts together with the presence of an additional methoxy group suggested
that the C-4 of 2 was attached by a methoxy group, which was reaffirmed by the key HMBC
correlation from OCH3 to C-4 (Figures S14 and S15, see Supporting Information). From the
biosynthetic standpoints, and in combination with the chemical evidences, the absolute
configurations of C-8 was determined to be identical to that of 1 by its resembling CD spectrum
with that of 1 (Figure 3A). The structure of 2 was then demonstrated as shown and named as
capitulactone B.
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Compound 3 was assigned a molecular formula of C18H18O5 as deduced from the
()-HRESIMS ion peak at m/z 337.1055 [M + Na]  (calcd 337.1046), as well as the 13C NMR
data. Three diagnostic signals observed at H 6.84 (H-2, d, J = 2.0 Hz), 6.83 (H-5, d, J = 8.3 Hz)
and 6.74 (H-6, dd, J = 8.3 and 2.0 Hz) in the 1H NMR spectrum were indicative of the presence of
a 1,3,4-trisubstituted phenyl group. Except for the phenyl group, the other NMR signals of 3 were
closely comparable to those of 2, indicating that the para-disubstituted phenyl group in 2 was
replaced by a 1,3,4-trisubstituted phenyl moiety in 3. Two quaternary carbon resonances at C
145.3 and 145.7 were assigned at C-3 and C-4, respectively, based on the strong HMBC
correlations from H-2 and H-6 to C-4 and from H-5 to C-3. A methoxyl and a hydroxyl groups
were positioned at C-4 and C-3, respectively, by the key HBMC correlations of OCH3/C-4 and
OH/C-2 (C 114.7), C-3, and C-4. The absolute configuration of 3 was determined as shown via
the same methods as those applied for compound 2.
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The biosynthetic pathways proposed for 1−3 were shown in Scheme 1. The biosynthesis was
initiated from the transformation of the lignin precursors, p-coumarate, to the key quinonemethide
intermediate,14 which subsequently reacted with p-coumarate to yield the key intermediate i.15
Decarboxylation of i would generate the intermediate ii with a 7′Z double bond. Then, the
successive oxidative reaction of ii and intramolecular nucleophilic and oxidative reactions of iii
would generate intermediate v. The intermediate vi was presumed to be derived from v via the
Baeyer-Villiger oxidation.16 Finally, a regioselective reduction of v would afford compound 1, and
compounds 2 and 3 would be further produced by a series of enzyme-catalytic modification of 1.
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Scheme 1. Hypothetical Biosynthetic Pathways Proposed for Compounds 1−3
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To fully determine the stereochemistry of 1, 2 and 3, a synthetic strategy involving an oxidation
- reduction reaction method as the key step was carried out. This would allow the rapid synthesis
of the three pairs of enantiomers, including 1a (8S), 1b (8R), 2a (8S), 2b (8R), 3a (8S) and 3b (8R).
This strategy will also facilitate the modular construction of a small library of stereo analogues.
Initially, we considered 2a and 2b as our synthetic target compounds. With respect to the
retrosynthetic analysis (Scheme 2) of 2a and 2b, it was envisioned that 2a (2b) could be easily
obtained from the precursor 4a (4b) through lindlar hydrogenation. We believed that 4a (4b)
could be constructed via the crucial oxidation - reduction method from benzodihydrofuran
compound 5a (5b) with a biomimetic synthesis consideration. 5a (5b) was expected to be
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prepared from 6a (6b) through copper-catalyzed etherification of aryl halides. Finally, the
cyclization precursor 6a (6b) could be synthesized through the assembly of epoxide 7a (7b) and
alkyne 8.
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Scheme 2. Retrosynthetic Analysis of 2a and 2b
With the above synthetic strategy in mind, we first synthesized the key intermediate 5a (5b)
(Scheme 3) for exploring the oxidation - reduction method. The synthesis began with
hydroiodination of commercially available materials 4-bromoveratrole 9 to provide phenyl iodide
10 in 85% yield under known conditions.17 So as to avoid the difficulty of removing the methyl
groups in the later stage, we removed the methyl groups and protected the hydroxy groups by TBS
to give compound 11. Synthesis of propylene oxide 13a (13b) commenced with the regioselective
ring opening of (R)-epichlorohydrin (12a) or (S)-epichlorohydrin (12b) with
2-bromophenyllithium species, which was prepared by iodoselective lithiation of
bromoiodobenzene derivative 11. Cleavage of the epoxide in 12a (12b) proceeded smoothly in the
presence of BF3ꞏOEt2 to provide exclusively the desired chlorohydrin 13a (13b).18 Then, epoxide
7a (7b) was formed in the presence of NaOH from 13a (13b). Addition of the lithium acetylide
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derived from 8 to epoxide 7a (7b) gave alcohol 6a (6b). With 6a (6b) in hand. We then
constructed dihydrobenzofuran compound 5a (5b) by employing the CuCl catalyzed
intramolecular etherification of aryl halides at reflux conditions.19
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Scheme 3. Synthesis of 5a and 5b
With essential precursor 5a (5b) in hand, we then devoted our effort for the construction of the
hepta-lactone ring system bearing a conjugated diene fragment utilizing the oxidation-reduction
reaction strategy (Scheme 4). We converted 5a (5b) to the hydrogenation precursor 4a (4b) in a
four-step sequence involving removal of TBS protecting groups with TBAF, the oxidation of
o-phenol to benzoquinone under ammonium nitrate (CAN), oxidation of benzoquinone to
anhydride under m-chloroperoxybenzoic acid (m-CPBA), and finally the in situ reduction of the
resultant anhydride with NaBH4.20 Notably, the synthesized benzoquinone and anhydride was not
required further purification due to the unstable nature. 4a (4b) was hydrogenated with lindlar's
catalyst to produce compound 2a (2b) in 90% yield.
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Scheme 4. Synthesis of 2a and 2b
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Extensive comparison showed that the NMR spectra of compounds 2a, 2b and natural product
(2) completely matched, indicating that their structures were the same and/or enantiomers. The
specific rotations [α]D18 = −11.9 (for 2a, c 0.12, MeOH) and +13.3 (for 2b, c 0.10, MeOH), further
indicated that the absolute configuration of natural product (2) was identical to that of the
synthetic 2a (8S).
Scheme 5. Synthesis of 1a (1b)
To fully determine the structure and absolute configuration of natural product (1, 3),
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compounds 1a (1b) and 3a (3b) were synthesized from 14 and 21 respectively applying the same
strategy (Scheme 5 and 6) herein replaced the hard-to-remove methyl group with MOM protection
attached to the benzene ring. The NMR spectra and specific rotations (for details, see Supporting
Information) of compounds 1a (1b) and 3a (3b) showed that natural product 1 and 3 are
corresponding to the synthetic 1a (8S) and 3a (8S) respectively. The synthesis results further
validated the structure and absolute configuration of the natural products.
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Scheme 6. Synthesis of 3a (3b)
Conclusion
In conclusion, this study identified three agent, Capitulactones AC, isolated from Curculigo
capitulata. Those Compounds featured an unprecedented hepta-lactone ring system with a
conjugated diene fragment and one chiral center. The absolute configuration of 1, 2 and 3 were
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validated through spectroscopic data analysis and biomimetic synthesis, which was successfully
achieved in 9-10 steps with a 14.8%, 12.7% and 10.3% overall yield respectively from the known
compounds, involving an oxidation - reduction reaction method as the key step to construct the
hepta-lactone ring scaffold.
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EXPERIMENTAL SECTION
General Experimental Procedures
Optical rotations were detected on an Autopol Ⅵ polarimeter at room temperature. UV spectra
were measured on a Shimadzu UV-2550 UV-visible spectrophotometer. IR spectra were recorded
on a Thermo IS5 spectrometer using KBr disks. NMR spectra were measured on a Bruker
AM-500 spectrometer with TMS as internal standard. ()-ESIMS and ()-HRESIMS analysis
were carried out on a Bruker Daltonics Esquire 3000 plus LC-MS instrument and a waters Q-TOF
Ultima mass spectrometer, respectively. Semipreparative HPLC was carried out on a Waters 1525
binary pump system with a Waters 2489 detector (210 nm) using a YMC−Pack ODS-A column
(250×10 mm, S-5 μm). Silica gel (200300 mesh, Qingdao Haiyang Chemical Co. Ltd), C18
reversed-phase silica gel (150200 mesh, Merck) and MCI gel (CHP20P, a kind of refined
polystyrene-based separation stuffing, 75150 m, Mitsubishi Chemical Industries, Ltd.),
D101-macroporous absorption resin (Shanghai Huangling Resin Co. Ltd.) were used for column
chromatography (CC). Pre-coated silica gel GF254 plates (Qingdao Haiyang Chemical Co. Ltd.)
were used for TLC detection. All solvents used for CC were of analytical grade (Shanghai
Chemical Reagents Co. Ltd.) and solvents used for HPLC were of HPLC grade (J & K Scientific
Ltd.). For the synthesis part, all commercially available reagents were used without further
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purification unless otherwise noted. Column chromatography was performed on silica gel
(200-300 mesh). NMR spectra were recorded on Bruker 400 MHz in the CDCl3 or DMSO-d6.
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Chemical shifts are reported as δ values relative to internal chloroform (δ 7.26 for H NMR and
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77.00 for 13C NMR) and DMSO -d6 (δ 2.50 for 1H NMR and 39.52 for 13C NMR). High resolution
mass spectra (HRMS) were obtained on a 4G mass spectrometer by using electrospray ionization
(ESI) analyzed by quadrupole time-of-flight (Q-TOF). Optical rotations were measured on a
Rudolph Autoplo IV polarimeter. IR spectra were recorded on a Thermo IS5 spectrometer using
KBr disks.
Plant Material. The roots of Curculigo capitulata was collected in May 2012 from Longlin
county of Guangxi province, People’s Republic of China, and authenticated by Prof. Shao-Qing
Tang of college of life science, Guangxi normal university. A voucher specimen has been
deposited in the Herbarium of Shanghai Institute of Materia Medica, Chinese Academy of
Sciences (Curcap-2012-5Y).
Isolation and Structural Elucidation of Capitulactones AC. The air-dried roots (9 kg) of
Curculigo capitulata were extracted with 95% ethanol at room temperature for three times. After
evaporation of the solvent under reduced pressure, the residue (500 g) was dissolved in 1 L water
and then partitioned with EtOAc (1 L  3). The EtOAc extract (200 g) was subject to column
chromatography (CC) over macroporous resin D-101 (EtOH-H2O, 50%, 80% and 95%) to get
three fractions. The 80% ethanol eluent was separated on a CC over MCI gel (MeOH-H2O, 50%
to 100%) to afford three fractions, and the 70% fraction (30 g) was then chromatographed on a
silica gel eluted with petroleum ether-acetone (15:1 to 1:3) to get five major subfractions (AE).
Fraction D was submitted to chromatography on a silica gel column eluted with CHCl3-MeOH to
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afford three fractions D-1 to D-3, the former of which was then fractionated on a reverse-phase
C-18 silica gel CC using MeOH-H2O system (60% to 100%) to get four major subfractions D-11
to D-14. Fraction D-12 was separated on a silica gel CC eluted with petroleum ether-ethyl acetate
to get five subfractions D-12-1 to D-12-5. The Fraction D-12-1 was then purified with
semipreparative HPLC (MeCN-H2O, 40%, 3ml/min) to yield compounds 1 (15 mg, tR = 14 min).
Fraction D-12-2 was first chromatographed on a silica gel column eluted with CDCl3-MeOH and
then purified with semipreparative HPLC (MeCN-H2O, 50%, 3ml/min) to yield compound 2 (8.2
mg, tR = 18 min). With the same procedure as fraction D-12-2, fraction D-12-3 provided
compound 3 (11 mg, MeCN-H2O, 50%, 3ml/min, tR = 16 min).
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Capitulactone A (1): white amorphous powder; [α]D20 10.7 (c 0.14, MeOH); 1H NMR (CDCl3),
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see Table S1 and C NMR (CDCl3), see Table S1; ()-ESIMS m/z 285.1 [M + H], 307.2 [M 
Na], 591.3 [2M  Na]; ()-ESIMS m/z 283.2 [M  H], 567.8[2M  H]; ()-HRESIMS m/z
283.0964 [M  H] (calcd for C17H15O4, 283.0976).
Capitulactone B (2): white amorphous powder; [α]D20 13.6 (c 0.14, MeOH); 1H NMR (CDCl3),
see Table S1 and 13C NMR (CDCl3), see Table S1; ()-ESIMS 299.2 [M + H], 321.2 [M  Na],
619.2 [2M  Na]; ()-HRESIMS m/z 619.2326 [2M  Na] (calcd for C31H42O10Na, 619.2302).
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Capitulactone C (3): white amorphous powder; [α]D 8.5 (c 0.15, MeOH); H NMR (CDCl3),
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see Table S1 and C NMR (CDCl3), see Table S1; ()-ESIMS m/z 315.2 [M + H], 337.2 [M 
Na], 651.2 [2M  Na]; ()-ESIMS m/z 313.1 [M  H]; ()-HRESIMS m/z 337.1055 [M  Na]
(calcd for C18H18O5Na, 337.1046).
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Total Syntheses of 2a and 2b
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1-Bromo-2-iodo-4,5-dimethoxybenzene (10). Compound 9 (20.0 g, 92.2 mmol) was dissolved in
acetonitrile (200mL) at room temperature. NIS (22.8 g, 101.3 mmol) and TMSCl (1.2 mL, 0.92
mmol) were added to this solution. The mixture was stirred continuously overnight, poured into
cold water (100 mL) and extracted with ethyl acetate (3 × 100 mL), dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by flash column
chromatography (hexanes/EtOAc, 16:1) to afford compound 10 (26.9 g, 85%) as a white solid. 1H
NMR (400 MHz, CDCl3) δ 7.19 (s, 1H), 7.04 (s, 1H), 3.822 (s, 3H), 3.818 (s, 3H). 13C {1H}NMR
(101 MHz, CDCl3) δ 149.8, 148.6, 122.0, 120.1, 115.2, 88.8, 56.2, 56.1. Consistent with the
literature report. 17
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((4-Bromo-5-iodo-1,2-phenylene)bis(oxy))bis(tert-butyldimethylsilane) (11). To a solution of
compound 10 (30 g, 87.7 mmol) in DCM (100 mL) was added BBr3 (17.0 mL, 175.4 mmol)
slowly over 5 minutes at 0 °C. After the completion of the reaction, water (50 mL) was added
slowly to quench the reaction. The mixture was extracted with DCM (3 × 50 mL), dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by
flash column chromatography (hexanes/EtOAc, 2:1) to give intermediate compound
4-bromo-5-iodobenzene-1,2-diol. To a solution of 4-bromo-5-iodobenzene-1,2-diol (25 g, 79.4
mmol) in DMF (200 mL) was added imidazole (16.2 g, 0.24 mol) and DMAP (0.97 g, 7.9 mmol).
After stirring for 5 min at room temperature, TBSCl (36.0 g, 0.24 mol) was added in portions.
After the completion of the reaction, the resulting solution was quenched with saturated aqueous
NH4Cl (20mL) and extracted with ethyl acetate (3 × 100 mL). The organic extracts were washed
with saturated aqueous NaCl (2 × 50 mL), dried over Na2SO4, and concentrated under reduced
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pressure. The residue was purified by flash column chromatography (hexanes/EtOAc, 16:1) to
give compound 11 (43.2 g, 91% for 2 steps) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.26
(s, 1H), 7.07 (s, 1H), 0.97 (s, 18H), 0.20 (s, 6H), 0.19 (s, 6H). 13C {1H}NMR (101 MHz, CDCl3) δ
148.1, 147.0, 131.6, 124.7, 120.2, 89.4, 25.9, 25.8, 18.4, -4.20, -4.22. Consistent with the literature
report.21
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(R)-1-(2-Bromo-4,5-bis((tert-butyldimethylsilyl)oxy)phenyl)-3-chloropropan-2-ol ((R)-13a).
To a solution of compound 11 (20 g, 36.8 mmol) in dry toluene (300 mL) Under argon atmosphere
was added n-BuLi (2.4 M, 15.3 mL, 36.8 mmol) at -78 °C. n-BuLi was added dropwise over 40
min at the rate that inner temperature was maintained under -75 °C. To the resulting viscous
suspension was added (R)-12a (2.9 mL, 36.8 mmol) dropwise over 5 min. After BF3ꞏOEt2 (4.6 mL,
36.8 mmol) was added rapidly, the reaction mixture was stirred for 5 min, after which time TLC
indicated complete consumption of 11. The reaction was quenched with saturated aqueous sodium
bicarbonate at -78 °C and let warm to room temperature. The resulting mixture was extracted with
ethyl acetate(3 × 100 mL). The combined organic extracts were washed with brine(2 × 50 mL),
dried over anhydrous Na2SO4, and filtered through thin pad of silica gel. The resulting filtrate was
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concentrated under reduced pressure to afford pure (R)-13a (16.9 g, 90%) as a white solid. [α]D
-5.0 (c 1.00, CH2Cl2); mp: 84–86 °C; 1H NMR (400 MHz, CDCl3) δ 7.00 (s, 1H), 6.79 (s, 1H),
4.12 (m, 1H), 3.67 (q, J = 11.2, 3.4 Hz, 1H), 3.52 (q, J = 11.2, 6.1 Hz, 1H), 2.89 (m, 2H), 0.981 (s,
9H), 0.976 (s, 9H), 0.20 (s, 6H) , 0.19 (s, 6H). 13C {1H}NMR (101 MHz, CDCl3) δ 146.6, 146.4,
129.1, 124.9, 123.6, 114.7, 70.7, 49.5, 40.0, 25.9, 25.8, 18.45, 18.40, -4.10, -4.15, -4.17, -4.21. IR
(KBr) νmax 3423, 3054, 2932, 2859, 1595, 1494, 1265, 842, 739cm-1；HRMS (ESI): calcd for
C21H39BrClO3Si2 [M + H]+ 509.1304, found 509.1302.
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(S)-1-(2-Bromo-4,5-bis((tert-butyldimethylsilyl)oxy)phenyl)-3-chloropropan-2-ol ((S)-13b).
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Prepared according to the above step. White solid (16.5 g, 88%). [α]D20 +4.0 (c 1.00, CH2Cl2); mp:
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82–84 °C; H NMR (400 MHz, CDCl3) δ 6.99 (s, 1H), 6.78 (s, 1H), 4.12 (m, 1H), 3.67 (q, J =
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11.2, 3.4 Hz, 1H), 3.52 (q, J = 11.2, 6.1 Hz, 1H), 2.89 (m, 2H), 2.18 (d, J = 5.4 Hz, 1H)(-OH),
0.98 (s, 9H), 0.97 (s, 9H), 0.193 (s, 6H) , 0.187 (s, 6H). 13C {1H}NMR (101 MHz, CDCl3) δ 146.6,
146.4, 129.1, 124.9, 123.6, 114.7, 70.7, 49.5, 40.0, 25.85, 25.81, 18.43, 18.38, -4.1, -4.17, -4.19,
-4.24. IR (KBr) νmax 3397, 3055, 2927, 2857, 1594, 1510, 1265, 846, 740cm-1；HRMS (ESI): calcd
for C21H39BrClO3Si2 [M + H]+ 509.1304, found 509.1302.
(R)-((4-Bromo-5-(oxiran-2-ylmethyl)-1,2-phenylene)bis(oxy))bis(tert-butyldimethylsilane)
((R)-7a). NaOH (862 mg, 21.6 mmol) was added to a solution of (R)-13a (11 g, 21.6 mmol) in
THF(100 mL) at room temperature. The reaction mixture was stirred at 25 °C for 1 h, then diluted
with water (20 mL) and extracted with ethyl acetate (3 × 50 mL). The organic extracts were
combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was
purified by flash column chromatography (hexanes/EtOAc, 32:1) to give (R)-7a (9.8 g, 96%) as a
colorless oil. [α]D20 -3.0 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.00 (s, 1H), 6.80 (s, 1H),
3.15 (dd, J = 7.2, 4.1 Hz, 1H), 2.93 – 2.84 (m, 2H), 2.78 (t, J = 4.4 Hz, 1H), 2.53 (dd, J = 4.8, 2.6
Hz, 1H), 0.983 (s, 9H), 0.978 (s, 9H), 0.20 (s, 12H). 13C {1H}NMR (101 MHz, CDCl3) δ 146.44，
146.37, 129.3, 124.7, 123.1, 114.6, 51.4, 46.8, 37.9, 25.90, 25.86, 18.5, 18.4, -4.1, -4.2. IR (KBr)
νmax 3054, 2931, 2858, 1687, 1596, 1494, 1265, 841, 741cm-1 HRMS (ESI): calcd for
C21H38BrO3Si2 [M + H]+ 473.1537, found 473.1538.
(S)-((4-Bromo-5-(oxiran-2-ylmethyl)-1,2-phenylene)bis(oxy))bis(tert-butyldimethylsilane)
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((S)-7b). Prepared according to the above step. Colorless oil (9.7 g, 95%). [α]D +2.0 (c 1.00,
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CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.00 (s, 1H), 6.79 (s, 1H), 3.16 (tdd, J = 5.3, 3.2, 2.0 Hz,
1H), 2.88 (dd, J = 5.3, 2.0 Hz, 2H), 2.80 – 2.76 (m, 1H), 2.54 (dd, J = 5.0, 2.7 Hz, 1H), 0.98 (s,
9H), 0.97 (s, 9H), 0.19 (s, 12H). 13C {1H}NMR (101 MHz, CDCl3) δ 146.4, 129.3, 124.7, 123.1,
114.6, 51.5, 46.8, 37.9, 25.90, 25.85, 18.5, 18.4, -4.1, -4.15, -4.21. IR (KBr) νmax 3053, 2931, 2859,
1596, 1494, 1265, 841, 741cm-1; HRMS (ESI): calcd for C21H38BrO3Si2 [M + H]+ 473.1537, found
473.1534.
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(S)-1-(2-Bromo-4,5-bis((tert-butyldimethylsilyl)oxy)phenyl)-5-(4-methoxyphenyl)pent-4-yn-2
-ol ((S)-6a). To a solution of compound 8 (2.8 g, 21.2 mmol) in dry THF (80 mL) under argon
atmosphere was added n-BuLi (2.4 M, 9.7 mL, 23.3 mmol) at -78 °C. The mixture was stirred at
-78 °C for 1 h, (R)-7a (10 g, 21.2 mmol) in anhydrous THF and BF3ꞏOEt2 (2.7 mL, 21.2 mmol)
was slowly added. After the completion of the reaction, the resulting solution was quenched with
water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic solution was
washed with saturated aqueous NaCl (20 mL), dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified by flash column chromatography
(hexanes/EtOAc, 8:1) to give (S)-6a (11.9 g, 93%) as a colorless oil. [α]D20 -33.0 (c 1.00, CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 7.40 – 7.34 (m, 2H), 7.00 (s, 1H), 6.83 (m, 3H), 4.15 – 4.04 (m,
1H), 3.81 (s, 3H), 3.00 (dd, J = 13.7, 5.9 Hz, 1H), 2.87 (dd, J = 13.7, 7.2 Hz, 1H), 2.67 (dd, J =
16.8, 5.0 Hz, 1H), 2.57 (dd, J = 16.8, 6.1 Hz, 1H), 2.06 (d, J = 5.1 Hz, 1H), 0.99 – 0.95 (m, 18H),
0.19 (m, 12H). 13C {1H}NMR (101 MHz, CDCl3) δ 159.3, 146.4, 146.3, 133.0, 130.0, 124.8,
123.7, 115.4, 114.8, 113.8, 84.1, 83.3, 69.7, 55.3, 41.9, 27.4, 25.9, 25.8, 18.41, 18.38, -4.1, -4.16,
-4.19, -4.23. IR (KBr) νmax 3443, 3052, 2956, 2931, 2895, 2859, 1607, 1509, 1442, 1385, 1263,
840, 740cm-1; HRMS (ESI): calcd for C30H46BrO4Si2 [M + H]+ 605.2113, found 605.2117.
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2-ol ((R)-6b). Prepared according to the above step. Colorless oil (11.7 g, 91%). [α]D +43.0 (c
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1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.8 Hz, 2H), 7.03 (s, 1H), 6.87 (s, 1H),
6.82 (d, J = 8.4 Hz, 2H), 4.13 (m, 1H), 3.78 (s, 3H), 3.03 (q, 1H), 2.90 (q, 1H), 2.63 (m, 2H), 2.38
– 2.24 (br, 1H), 1.00 (s, 9H), 0.99 (s, 9H), 0.22 (s, 12H). 13C {1H}NMR (101 MHz, CDCl3) δ
159.1, 146.3, 146.1, 132.9, 130.1, 124.7, 123.7, 115.4, 114.8, 113.7, 84.1, 83.2, 69.5, 55.1, 41.8,
27.3, 25.79, 25.76, 18.31, 18.28, -4.19, -4.23, -4.27, -4.31. IR (KBr) νmax 3437, 3053, 2956, 2931,
2898, 2859, 1607, 1509, 1442, 1385, 1264, 841, 740cm-1; HRMS (ESI): calcd for C30H46BrO4Si2
[M + H]+ 605.2113, found 605.2114.
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(S)-((2-(3-(4-Methoxyphenyl)prop-2-yn-1-yl)-2,3-dihydrobenzofuran-5,6-diyl)bis(oxy))bis(ter
t-butyldimethylsilane) ((S)-5a). To a solution of (S)-6a (8.2 g, 13.6 mmol) in dry toluene (100
mL) under argon atmosphere, NaH (60%) (667 mg, 16.7 mmol) was added. The mixture was
stirred at 40 °C for 15 min. Then, the mixture was cooled to room temperature and CuCl (54 mg,
0.54 mmol) was added to the solution. The suspension was stirred for 6 h at 110 °C and after this
time, the mixture was filtered through Celite®. Then, the mixture was purified by flash
chromatography (hexanes/EtOAc, 16:1) to give (S)-5a (6.7 g, 95%) as a colorless oil. [α]D20 +40.0
(c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H),
6.65 (s, 1H), 6.34 (s, 1H), 4.93 (m, 1H), 3.80 (s, 3H), 3.29 (dd, J = 15.3, 8.9 Hz, 1H), 3.06 (dd, J =
15.3, 6.6 Hz, 1H), 2.82 (m, 2H), 0.983 (s, 9H), 0.976 (s, 9H), 0.19 (s, 6H) , 0.16 (s, 6H). 13C
{1H}NMR (101 MHz, CDCl3) δ 159.3, 153.4, 146.3, 140.5, 133.0, 117.8, 116.9, 115.6, 113.81,
102.7, 83.7, 82.2, 81.3, 55.2, 35.0, 26.5, 26.0, 25.98 , 18.5, 18.4, -4.0, -4.07, -4.14. IR (KBr) νmax
3054, 2957, 2930, 2858, 1608, 1509, 1423, 1362, 1265, 1166, 838, 742cm-1；HRMS (ESI): calcd
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for C30H45O4Si2 [M + H]+ 525.2851, found 525.2854.
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(R)-((2-(3-(4-Methoxyphenyl)prop-2-yn-1-yl)-2,3-dihydrobenzofuran-5,6-diyl)bis(oxy))bis(te
rt-butyldimethylsilane) ((R)-5b). Prepared according to the above step. Colorless oil (6.0 g,
92%). [α]D20 -27.0 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.7 Hz, 2H), 6.80
(d, J = 8.8 Hz, 2H), 6.65 (s, 1H), 6.34 (s, 1H), 4.98 – 4.89 (m, 1H), 3.80 (s, 3H), 3.29 (dd, J = 15.4,
8.9 Hz, 1H), 3.05 (dd, J = 15.3, 6.6 Hz, 1H), 2.82 (m, 2H), 0.98 (s, 9H), 0.97 (s, 9H), 0.17 (m,
12H). 13C {1H}NMR (101 MHz, CDCl3) δ 159.2, 153.4, 146.2, 140.5, 133.0, 117.8, 117.0, 115.5,
113.8, 102.6, 83.7, 82.1, 81.3, 55.2, 34.9, 26.5, 25.98, 25.96, 18.5, 18.4, -4.06, -4.09, -4.16, -4.18.
IR (KBr) νmax 3052, 2956, 2931, 2858, 1608, 1509, 1424, 1362, 1265, 1166, 838, 740cm-1；HRMS
(ESI): calcd for C30H45O4Si2 [M + H]+ 525.2851, found 525.2853.
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(S)-2-(3-(4-Methoxyphenyl)prop-2-yn-1-yl)-2,3-dihydrofuro[2,3-d]oxepin-7(5H)-one ((S)-4a).
To a solution of (S)-5a (1.1 g, 2.1 mmol) in THF (50 mL) was added tetrabutylammonium fluoride
(2 M in THF, 1.1 mL), and the resultant mixture was stirred at 0 °C for 5 min. The reaction was
quenched with saturated aqueous NH4Cl (10 mL), and the resultant mixture was extracted with
ethyl acetate (3 × 20 mL). The organic extracts were washed with saturated aqueous NaCl (2 × 20
mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was
dissolved in MeCN (20 mL), and Ceric ammonium nitrate (1.0 M in H2O, 4.6 mL) was added
dropwise at 0 °C. Ethyl acetate (10 mL) was added to the reaction immediately, and the resultant
mixture was extracted with ethyl acetate (3 × 20 mL). The organic extracts were washed with
saturated aqueous NaCl (2 × 20 mL), dried over Na2SO4, filtered and concentrated under reduced
pressure to give the crude product benzoquinone. The benzoquinone was dissolved in anhydrous
CH2Cl2 at 0 °C, m-CPBA (75%) (482 mg, 2.1 mmol) was added to the solution. After the
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completion of the reaction, the solvent was removed under reduced pressure. The residue was
quickly purified through thin pad of silica gel (hexanes/EtOAc, 2:1) to give crude product
anhydride as a yellow oil. The crude product is used directly for the next step. The crude product
anhydride was added to a solution of NaBH4 (30 mg, 0.8 mmol) in 5 mL of dry THF at 0 °C. After
the completion of the reaction, the reaction was treated by slow addition of 1.0 M HCl until all the
solid had dissolved. The resulting solution was extracted with ethyl acetate (3 × 10 mL). The
combined organic solution was washed with saturated aqueous NaCl (2 × 10 mL), dried over
anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by
flash column chromatography (hexanes/EtOAc, 8:1) to give (S)-4a (143 mg, 22% for 4 steps) as a
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colorless oil. [α]D20 +13.0 (c 1.00, CH2Cl2); H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.8 Hz,
2H), 6.82 (d, J = 8.8 Hz, 2H), 6.43 – 6.37 (m, 1H), 5.73 (s, 1H), 4.80 – 4.72 (m, 1H), 4.55 (m, 2H),
3.80 (s, 3H), 3.09 (dd, J = 15.6, 7.3 Hz, 1H), 2.90 (dd, J = 15.5, 5.8 Hz, 1H), 2.80 (m, 2H). 13C
{1H}NMR (101 MHz, CDCl3) δ 169.0, 166.2, 159.6, 140.3, 133.0, 127.5, 114.9, 113.9, 95.9, 83.4,
81.7, 80.6, 62.5, 55.3, 35.2, 25.9. IR (KBr) νmax 3055, 2987, 2928, 1688, 1606, 1510, 1422, 1265,
1182, 896, 835, 739, 705cm-1；HRMS (ESI): calcd for C18H17O4 [M + H]+ 297.1121, found
297.1124.
(R)-2-(3-(4-Methoxyphenyl)prop-2-yn-1-yl)-2,3-dihydrofuro[2,3-d]oxepin-7(5H)-one ((R)-4b).
Prepared according to the above steps. Colorless oil (124 mg, 19% for 4 steps). [α]D20 -12.0 (c 1.00,
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 6.43 –
6.37 (m, 1H), 5.72 (s, 1H), 4.80 – 4.71 (m, 1H), 4.54 (m, 2H), 3.79 (s, 3H), 3.09 (dd, J = 15.6, 7.3
Hz, 1H), 2.90 (dd, J = 15.5, 5.7 Hz, 1H), 2.79 (m, 2H). 13C {1H}NMR (101 MHz, CDCl3) δ 169.0,
166.2, 159.5, 140.2, 133.0, 127.5, 114.8, 113.9, 95.9, 83.3, 81.7, 80.5, 62.5, 55.2, 35.2, 25.9. IR
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(KBr) νmax 3055, 2987, 2927, 2854, 1691, 1607, 1510, 1422, 1265, 1182, 896, 835, 740, 705cm-1；
HRMS (ESI): calcd for C18H17O4 [M + H]+ 297.1121, found 297.1123.
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(S, Z)-2-(3-(4-Methoxyphenyl)allyl)-2,3-dihydrofuro[2,3-d]oxepin-7(5H)-one ((S)-2a). To a
solution of (S)-4a (58 mg, 0.20 mmol) in ethyl acetate (5 mL ) was added quinoline (5.3 μL, 10%
in weight) followed by Lindlar’s catalyst (11.6 mg, 20% in weight). This solution was stirred
under a balloon of hydrogen for 1.5 h. The reaction mixture was filtered through a plug of silica
and the solvent removed in vacuo; purification by Silver nitrate silica gel column chromatography
yielded (S)-2a (52 mg, 90%) as a colourless oil. [α]D18 -11.9 (c 0.12, MeOH); 1H NMR (400 MHz,
CDCl3) δ 7.19 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 6.56 (d, J = 11.6 Hz, 1H), 6.38 – 6.31
(m, 1H), 5.69 (s, 1H), 5.55 (dt, J = 11.7, 7.2 Hz, 1H), 4.66 – 4.59 (m, 1H), 4.57 (dd, J = 8.6, 3.6
Hz, 2H), 3.82 (s, 3H), 2.95 (dd, J = 15.3, 7.2 Hz, 1H), 2.82 – 2.72 (m, 1H), 2.72 – 2.56 (m, 2H).
13C {1H}NMR (101 MHz, CDCl3) δ 169.1, 166.2, 158.6, 140.6, 132.1, 129.9, 129.3, 127.3, 123.4,
113.8, 95.7, 82.6, 62.5, 55.3, 35.6, 33.8. IR (KBr) νmax 2916, 2850, 1681, 1607, 1516, 1254, 1174,
1029 cm-1；HRMS (ESI): calcd for C18H19O4 [M + H]+ 299.1278, found 299.1281.
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(R, Z)-2-(3-(4-Methoxyphenyl)allyl)-2,3-dihydrofuro[2,3-d]oxepin-7(5H)-one ((R)-2b).
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Prepared according to the above step. Colorless oil (50 mg, 90%). [α]D +13.3 (c 0.10, MeOH);
1H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 6.56 (d, J = 11.6
Hz, 1H), 6.38 – 6.30 (m, 1H), 5.69 (s, 1H), 5.55 (dt, J = 11.6, 7.2 Hz, 1H), 4.68 – 4.59 (m, 1H),
4.59 – 4.50 (m, 2H), 3.81 (s, 3H), 2.95 (dd, J = 15.5, 6.9 Hz, 1H), 2.83 – 2.72 (m, 1H), 2.71 – 2.56
(m, 2H). 13C {1H}NMR (101 MHz, CDCl3) δ 169.1, 166.2, 158.6, 140.6, 132.1, 129.9, 129.3,
127.3, 123.4, 113.8, 95.7, 82.6, 62.5, 55.3, 35.6, 33.8. IR (KBr) νmax 2916, 2847, 1681, 1609, 1516,
1251, 1180, 1029 cm-1；HRMS (ESI): calcd for C18H19O4 [M + H]+ 299.1278, found 299.1280.
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Total Syntheses of 1a, 1b, 3a and 3b (for details, see Supporting Information)
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge via the Internet at http://pubs.acs.org
NMR spectroscopic data for 1‒3; Specific optical rotation of natural products and corresponding
synthetic compounds; CD curves of compounds 1, 1a, 1b, 2, 2a, 2b, 3, 3a, and 3b; 1D and 2D
NMR, ESIMS, HRESIMS, and IR spectra of compounds 1–3; Total syntheses of 1a, 1b, 3a and
3b; Copies of 1H and 13C NMR spectra of synthetic compounds.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: liying@lzu.edu.cn
*E-mail: jmyue@simm.ac.cn
Author Contributions
§Song Li, Jin-Hai Yu and Yao-Yue Fan contributed equally to this work
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial supports of the National Natural Science Foundation (Nos. 21772213; 21772079;
21472078) and the Drug Innovation Major Project (2018ZX09711001-001-005) of the P. R. China
are highly acknowledged.
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