Structural Elucidation and Total Synthesis of Three 9-Norlignans from

Mar 20, 2019 - Capitulactones A-C, three unprecedented 9-norlignans featuring a unique 3,5-dihydrofuro[2,3-d]oxepin-7(2H)-one scaffold, were isolated ...
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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 Li, and Jian-min Yue J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00170 • Publication Date (Web): 20 Mar 2019 Downloaded from http://pubs.acs.org on March 20, 2019

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The Journal of Organic Chemistry

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*,‡ †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 1   

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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 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  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 deficiency. In the 1H 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 detail, analysis of the 1H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 3   

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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 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 at m/z 619.2326 [2M + Na]+ (calcd 619.2302) and the 13C NMR data. Comparison of the 1H and 13

C 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

13

C 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.

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 

 

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 7   

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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.

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

2-bromophenyllithium

(R)-epichlorohydrin species,

which

(12a) was

or

prepared

(S)-epichlorohydrin by

iodoselective

(12b) lithiation

with 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 8   

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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

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. 9   

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Scheme 4. Synthesis of 2a and 2b

 

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), 10   

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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.

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 11   

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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.

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. Chemical shifts are reported as δ values relative to internal chloroform (δ 7.26 for 1H NMR and 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 13   

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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). Capitulactone A (1): white amorphous powder; [α]D20 10.7 (c 0.14, MeOH); 1H NMR (CDCl3), see Table S1 and 13C 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). Capitulactone C (3): white amorphous powder; [α]D20 8.5 (c 0.15, MeOH); 1H NMR (CDCl3), see Table S1 and 13C 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 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 ((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 15   

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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 (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 concentrated under reduced pressure to afford pure (R)-13a (16.9 g, 90%) as a white solid. [α]D20 -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. 16   

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(S)-1-(2-Bromo-4,5-bis((tert-butyldimethylsilyl)oxy)phenyl)-3-chloropropan-2-ol

((S)-13b).

Prepared according to the above step. White solid (16.5 g, 88%). [α]D20 +4.0 (c 1.00, CH2Cl2); mp: 82–84 °C; 1H NMR (400 MHz, CDCl3) δ 6.99 (s, 1H), 6.78 (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), 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) ((S)-7b). Prepared according to the above step. Colorless oil (9.7 g, 95%). [α]D20 +2.0 (c 1.00, 17   

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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. (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); 1

H 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).

13

C {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. 18   

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(R)-1-(2-Bromo-4,5-bis((tert-butyldimethylsilyl)oxy)phenyl)-5-(4-methoxyphenyl)pent-4-yn2-ol ((R)-6b). Prepared according to the above step. Colorless oil (11.7 g, 91%). [α]D20 +43.0 (c 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. (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 19   

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for C30H45O4Si2 [M + H]+ 525.2851, found 525.2854. (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. (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 20   

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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 colorless oil. [α]D20 +13.0 (c 1.00, CH2Cl2); 1H 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 21   

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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. (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). 13

C {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. (R, Z)-2-(3-(4-Methoxyphenyl)allyl)-2,3-dihydrofuro[2,3-d]oxepin-7(5H)-one ((R)-2b). Prepared according to the above step. Colorless oil (50 mg, 90%). [α]D18 +13.3 (c 0.10, MeOH); 1

H 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. 22   

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Total Syntheses of 1a, 1b, 3a and 3b (for details, see Supporting Information)

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. AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected] *E-mail: [email protected]    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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