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. 2020 Mar 9;5(10):5589–5600. doi: 10.1021/acsomega.0c00558

Palladium-Catalyzed Synthesis and Anticancer Activity of Paclitaxel–Dehydroepiandrosterone Hybrids

Sheng-Jie Lou †, Xiao-Huan Li †, Xian-Li Zhou †, Dong-Mei Fang ‡,*, Feng Gao †,*
PMCID: PMC7081646  PMID: 32201853

Abstract

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According to the activity–structure relationship of the C-13 side chain in paclitaxel or docetaxel, eighteen novel paclitaxel–dehydroepiandrosterone (DHEA) hybrids were designed and synthesized by Pd(II)-catalyzed Suzuki–Miyaura cross-coupling of 17-trifluoromethanesulfonic enolate-DHEA with different aryl boronic acids. The in vitro anticancer activity of the hybrids against a human liver cancer cell line (HepG-2) was evaluated by MTT assay, showing that most of these hybrids possessed moderate antiproliferative activity against the HepG-2 cancer cell line. Among these hybrids, three ones (7b, 7g, and 7i) with ortho-substituents in the phenyl group of the D-ring of DHEA analogues exhibited moderate anticancer activity. The optimal compound 7i showed superior anticancer activity against the HepG-2 cell line with an IC50 value of 26.39 μM.

Introduction

Paclitaxel (Taxol), isolated from the bark of Taxus brevifolia Nutt in the late 1960s,1 and its semisynthetic derivatives docetaxel (Taxotere) and cabazitaxel (Jevana) (Figure 1) currently serve as the most widely used clinical antitumor drugs against breast cancer, ovarian cancer, non-small cell lung cancer, and prostate cancer, among various chemotherapeutic agents.2 They are known to exert their therapeutic effect by their ability to accelerate the polymerization of tubulin and stabilize the resultant microtubules, which leads to apoptosis through a cell-signaling cascade.3−5 Because the significant role of taxoids in the field of anticancer and their undesirable side effects as well as drug resistance, numerous endeavors has been devoted to in-depth research on the structure–activity relationships (SARs) of paclitaxel to reveal the minimal structural requirements essential for biological activity and develop next-generation taxoid anticancer agents with better pharmacological properties and improved activity.2,6,7 As a result of the SAR studies, the oxetane D-ring and unique C-13 side chains of paclitaxel were indispensable active groups,8−12 and it has been justified by a range of successful studies of paclitaxel mimics that the complex taxane skeleton was replaced by a structurally simplified core but retained part of the three-dimensional configuration and phenylisoserine side chain of paclitaxel.13−17

Figure 1.

Figure 1

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Structures of paclitaxel, docetaxel, cabazitaxel, and abiraterone.

Currently, a good deal of bioactive taxoid mimics have resulted from modifications of the functional groups on the taxane baccatin core or modification of the size of the carbon rings contained within the molecule.2 By contrast, less attention has been paid to the hybridization of paclitaxel with other biologically active natural products. In 2000, Wandless et al.18 reported six paclitaxel–daunorubicin hybrids, and all of them displayed cytotoxic activity, although less than the parent monomers. In 2005, Guénard et al.16 reported eight paclitaxel-steroidal hybrids bearing the phenylisoserine side chain to mimic “T-form” docetaxel. Their cytotoxicity against the KB cell line and MCF-7 cell line was not as excellent as that of docetaxel and did not show any inhibitory activity for microtubule disassembly. Although the above studies did not render any taxoid mimic with improved anticancer activity, they revealed that paclitaxel–natural product-based hybrids were potential agents which could be possibly extended and strengthen the medical utility of Taxol. Furthermore, the highly complex structure of paclitaxel, especially its baccatin component, prevents the large-scale production of synthetic paclitaxel, which makes paclitaxel prohibitively expensive. Therefore, the combination of the minimal pharmacophore of the taxoid (the C-13 phenylisoserine side chain) with other accessible taxane skeleton-like natural compounds to generate a baccatin-free compound with a taxane-like conformation which retains appreciable antitumor activity is necessary and exciting.

In our previous studies,8 assays for antiproliferative activity indicated that paclitaxel mimics possessing only C-13 side chains and oxetane D-ring structures showed moderate antitumor activities. This result encouraged us to explore other paclitaxel mimics with both C-13 side chains and widely distributed paclitaxel-like natural skeletons. Kingston et al.19 synthesized twelve steroid-linked Taxol analogues as potential anticancer drugs. They revealed that all conjugates were cytotoxic to the A2870 ovarian cancer cell line, although less so than Taxol. Inspired by this, we envisioned searching for more steroid analogues as the substituents of the baccatin core of Taxol. Dehydroepiandrosterone (DHEA) is a steroidal hormone which aids in the prevention of cancer in rodents. Studies show that low circulating levels of DHEA have been associated with a higher incidence of breast cancer in women.20 In addition to its economical and accessible properties, the conformation and structure of DHEA are similar to those of taxane. Most important of all, abiraterone (Figure 1), formed by introducing a nitrogen heterocyclic ring into the D-ring of DHEA, has been used to treat cancer in clinic.21 There may be potential advantages for hybrid molecules if both drugs can be deactivated as the result of linking function and then released together.18 Accordingly, all the abovementioned benefits encourage us to synthesize paclitaxel–DHEA mimic hybrids to extend and strengthen the therapeutic use of paclitaxel for paclitaxel-resistant or paclitaxel-insensitive tumors. Herein, we reported the synthesis and in vitro anticancer activity of eighteen paclitaxel–DHEA hybrids, in which the intricate baccatin core is structurally replaced by DHEA analogues. In the synthesis strategy, the Suzuki–Miyaura reaction which is known for the formation of Csp2–Csp2 bonds was used as a key step to introduce different aromatic chains in the D-ring of DHEA to increase the diversity of this natural product. It is worth mentioning that this reaction is mainly used in the total synthesis of natural products;22−26 rare examples of direct modification of natural compounds with this reaction have been reported.27,28

Results and Discussion

Chemistry

A series of novel hybrids consisting of DHEA mimic subunits have been designed and synthesized to replace the paclitaxel baccatin scaffold. The preparation of the hybrids is outlined in Scheme 1.

Scheme 1. Synthesis of the Designed Paclitaxel Hybrids 7a–7r.

Scheme 1

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Starting from DHEA, masking of the free hydroxy group as a silyl ether, followed by treatment with PhN(Tf)2 and potassium bis(trimethylsilyl)amide (KHMDS) at −78 °C, provided triflate 2. Next, the famous Suzuki–Miyaura reaction which is widely used for the formation of Csp2–Csp2 bonds was carried out on the triflate 2 as a key step to cross-couple precursor 2 with boronic acid under the catalysis of PdCl2(PPh3)2 to access the targets 3a–3q. After deprotection of the 3-TBS group, we focused on synthesizing the paclitaxel–DHEA hybrids. The DHEA analogues 4a–4q were subjected to esterification with the purchased oxazolidinecarboxylic acids 5a or 5b,29 which resulted in the formation of oxazolidinecarboxylate 6a–6r (Scheme 1). Treatment of the intermediates 6a–6r with p-toluenesulfonic acid yielded eighteen paclitaxel–DHEA hybrids 7a–7r in 60–85% yields.

Biological Activity Evaluation

The eighteen newly synthesized hybrids were evaluated in vitro for their anticancer activity against a human tumor cell line (HepG-2) by MTT assay. The most interesting results are presented in Table 1. All the hybrids showed less anticancer activity than the positive control Taxol. Three ones (7b, 7g, and 7i) with ortho-substituents in the phenyl group of the D-ring of DHEA analogues indicated moderate anticancer activity, better than that of the others. Specifically, compound 7i exhibited the best anticancer activity against cell line HepG-2 with an IC50 value of 26.39 μM.

Table 1. Anticancer Activity Evaluation of Synthesized Hybrids.

compound IC50 (μM) HepG-2 compound IC50 (μM) HepG-2
7a 81.88 7j >300
7b 35.23 7k 81.61
7c 56.69 7l 153.66
7d 73.37 7m 67.72
7e >300 7n 128.86
7f 69.35 7o 125.63
7g 34.5 7p >300
7h 46.78 7q >300
7i 26.39 7r 125.63
Taxol 0.78    
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Conclusions

To summarize, eighteen novel paclitaxel–DHEA hybrids were designed and synthesized according to the SARs of Taxol and our previous studies,8 using the Suzuki–Miyaura reaction as a key step to directly introduce different aromatic chains in the D-ring of DHEA. The MTT assay showed all the hybrids displayed less anticancer activity than the positive control Taxol. Three ones (7b, 7g, and 7i) with ortho-substituents in the phenyl group of the D-ring of DHEA analogues indicated moderate anticancer activity, better than that of the others. The results may give inspiration and guide the following modification of paclitaxel-like hybrids with improved anticancer activity. The use of a baccatin-free hybrid component might be an effective strategy to establish a paclitaxel-based hybrid library.

Experimental Section

Chemistry

Materials and General Method

Unless otherwise noted, the reagents are commercially available and used without further purification. Synthesized compounds were purified by chromatography on silica gel (200–300 mesh) purchased from Qingdao Haiyang Chemical Co., Ltd. NMR spectra were recorded on a Bruker AV 600 or 400 NMR spectrometer in CDCl3 with tetramethylsilane as the internal standard; chemical shifts (δ) were reported in ppm values and J in Hz. HR-ESI-MS data were measured using a Q-TOF micro mass spectrometer (Waters).

Preparation of Compound 1

A solution of DHEA (10.4 mmol, 1.0 equiv), imidazole (31.2 mmol, 3.0 equiv), and 4-N-dimethylaminopyridine (1.04 mmol, 0.1 equiv) in dry dichloromethane (30 mL) was stirred at room temperature for 5 min. Then, tert-butyldimethylsilyl chloride (20.8 mmol, 2.0 equiv) was added to the mixed solution at 40 °C and the resultant mixture was stirred at the same temperature for 2 h until thin-layer chromatography showed complete consumption of the starting compound. Then, the reaction mixture was extracted with water and ethyl acetate (EtOAc) three times. The organic phase was washed with brine water and dried over Na2SO4. After removal of the solvent, the residue was purified by silica gel column chromatography (EtOAc/petroleum ether, 1:10) to afford compound 1 as a white solid in 90% yield. The 1H NMR data are consistent with the reported literature.30

Preparation of Compound 2

KHMDS [0.5 M in tetrahydrofuran (THF), 3 mL, 1.5 mmol, 3.0 equiv] was added to the mixture of compound 1 (0.5 mmol, 1.0 equiv) and PhN(Tf)2 (0.75 mmol, 1.5 equiv) in dry THF at −78 °C and the resultant mixture was stirred at the same temperature for 2 h and then neutralized with saturated NH4Cl (aq.). The mixture was extracted with EtOAc three times. The organic phase was washed with water and brine and dried over Na2SO4. After removal of the solvent, the crude mixture was purified by silica gel column chromatography (EtOAc/petroleum ether, 1:50) to afford the desired triflate 2 as a white solid, yield 65%. The 1H NMR data are consistent with the reported literature.31

General Procedure for the Compounds 3a–3q

A suspension of compound 2 (0.1 mmol, 1.0 equiv), boronic acid compound (0.1 mmol, 1 equiv), Na2CO3 (0.125 mmol, 1.25 equiv) and PdCl2(PPh3)2 (0.003 mmol, 0.03 equiv) in toluene (2 mL), EtOH (0.4 mL), and water (1 mL) was stirred at 75 °C under argon for 0.5 h. Then, the mixture was added to saturated NaHCO3 aq. (5.0 mL) and extracted with excess EtOAc three times. The organic phase was washed with water and brine and dried over Na2SO4. The solvent was removed and the crude mixture was purified by silica gel column chromatography (EtOAc/petroleum ether, 1:20) to obtain the desired compounds 3a–3q as a white solid, yield 60–90%.

Compound 3a, yield 60.0%: 1H NMR (400 MHz, CDCl3): δ 7.00 (s, 2H), 6.89 (s, 1H), 5.88 (d, J = 1.2 Hz, 1H), 5.37 (d, J = 5.2 Hz, 1H), 3.76–3.25 (m, 1H), 2.31 (s, 6H), 2.31–2.16 (m, 3H), 2.13–1.98 (m, 3H), 1.87–1.34 (m, 11H), 1.07 (s, 3H), 1.06 (s, 3H), 0.91 (s, 9H), 0.08 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 155.1, 142.0, 137.6 × 2, 137.4, 128.6, 127.0, 124.7 × 2, 121.1, 72.8, 57.9, 50.7, 47.3, 43.0, 37.5, 36.9, 35.6, 32.2, 31.8, 31.7, 30.7, 26.1 × 3, 21.6 × 2, 21.1, 19.5, 18.4, 16.8, −4.4 × 2. HRMS (ESI) m/z: calcd for C33H51OSi+, 491.3704; found, 491.3766 M + H+.

Compound 3b, yield 72%: 1H NMR (400 MHz, CDCl3): δ 7.21–7.16 (m, 3H), 7.11–7.01 (m, 1H), 5.89 (dd, J = 3.1, 1.6 Hz, 1H), 5.39–5.33 (m, 1H), 3.57–3.43 (m, 1H), 2.34 (s, 3H), 2.31–2.16 (m, 3H), 2.13–2.00 (m, 3H), 1.86–1.42 (m, 11H), 1.06 (s, 3H), 1.05 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 155.1, 142.1, 137.7, 137.4, 128.1, 127.6, 127.6, 127.2, 123.9, 121.1, 72.8, 57.9, 50.7, 47.4, 43.0, 37.5, 36.9, 35.6, 32.2, 31.8, 31.7, 31.7, 30.6, 26.1 × 3, 21.1, 19.5, 18.2, 16.8, −4.4 × 2. HRMS (ESI) m/z: calcd for C32H49OSi+, 477.3547; found, 477.3550 M + H+.

Compound 3c, yield 70%: 1H NMR (400 MHz, CDCl3): δ 7.28 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 5.87 (s, 1H), 5.36 (d, J = 5.2 Hz, 1H), 3.56–3.44 (m, 1H), 2.34 (s, 3H), 2.32–2.16 (m, 3H), 2.12–1.97 (m, 3H), 1.85–1.22 (m, 11H), 1.07 (s, 3H), 1.09–1.03 (m, 3H, overlapped), 1.05 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 154.8, 142.0, 136.5, 134.6, 129.0 × 2, 126.7, 126.5 × 2, 121.1, 72.8, 57.8, 50.7, 47.3, 43.0, 37.5, 36.9, 35.6, 32.2, 31.8, 31.7, 30.6, 26.1 × 3, 21.3, 21.1, 19.5, 18.4, 16.7, −4.4 × 2. HRMS (ESI) m/z: calcd for C32H49OSi+, 477.3547; found, 477.3548 M + H+.

Compound 3d, yield 79%: 1H NMR (400 MHz, CDCl3): δ 7.77 (s, 2H), 7.72 (s, 1H), 6.11 (s, 1H), 5.39–5.33 (m, 1H), 3.54–3.44 (m, 1H), 2.35–2.24 (m, 2H), 2.24–2.16 (m, 1H), 2.14–1.98 (m, 3H), 1.86–1.42 (m, 11H), 1.07 (s, 3H), 1.07 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 152.6, 142.1, 139.5, 131.7, 131.4, 126.6 × 3, 124.9, 122.2, 120.9, 120.4, 72.7, 57.8, 50.3, 47.5, 43.0, 37.4, 36.9, 35.3, 32.2, 32.0, 31.6, 30.6, 26.1 × 3, 21.0, 19.5, 18.4, 16.8, −4.5 × 2. HRMS (ESI) m/z: calcd for C33H45F6OSi+, 599.3138; found, 599.3159 M + H+.

Compound 3e, yield 75%: 1H NMR (400 MHz, CDCl3): δ 7.38–7.28 (m, 2H), 6.98 (t, J = 8.8 Hz, 2H), 5.85 (d, J = 1.2 Hz, 1H), 5.39–5.33 (m, 1H), 3.57–3.36 (m, 1H), 2.36–2.16 (m, 3H), 2.11–1.99 (m, 3H), 1.85–1.37 (m, 11H), 1.06 (s, 3H), 1.03 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 163.2, 160.8, 154.0, 142.0, 133.6, 133.5, 128.4, 127.2, 121.1, 115.2, 114.9, 72.7, 57.8, 50.6, 47.3, 43.0, 37.5, 36.9, 35.5, 32.2, 31.7 × 2, 30.6, 26.1 × 3, 21.0, 19.5, 18.4, 16.7, −4.5 × 2. HRMS (ESI) m/z: calcd for C32H46F3OSi+, 531.3265; found, 531.3253 M + H+.

Compound 3f, yield 90%: 1H NMR (400 MHz, CDCl3): δ 7.32–7.23 (m, 4H), 5.91 (dd, J = 2.8, 1.6 Hz, 1H), 5.57–5.13 (m, 1H), 3.74–3.34 (m, 1H), 2.34–2.16 (m, 3H), 2.11–1.94 (m, 3H), 1.88–1.19 (m, 11H), 1.06 (s, 3H), 1.03 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 153.8, 142.0, 135.9, 132.6, 128.4 × 2, 128.1 × 2, 128.0, 121.0, 72.7, 57.8, 50.6, 47.3, 43.0, 37.4, 36.9, 35.5, 32.2, 31.8, 31.7, 30.6, 26.1 × 3, 21.0, 19.5, 18.4, 16.7, −4.5 × 2. HRMS (ESI) m/z: calcd for C31H46ClOSi+, 497.3001; found, 497.3018 M + H+.

Compound 3g, yield 89%: 1H NMR (400 MHz, CDCl3): δ 7.22 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.94–6.91 (m, 1H), 6.79 (dd, J = 8.4, 2.4 Hz, 1H), 5.95–5.91 (m, 1H), 5.39–5.34 (m, 1H), 3.81 (s, 3H), 3.56–3.46 (m, 1H), 2.37–2.16 (m, 3H), 2.15–1.96 (m, 3H), 1.87–1.33 (m, 11H), 1.07 (s, 3H), 1.06 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 159.5, 154.8, 142.0, 138.9, 129.1, 127.7, 121.1, 119.4, 112.7, 112.1, 72.7, 57.8, 55.3, 50.6, 47.4, 43.0, 37.4, 36.9, 35.6, 32.2, 31.7 × 2, 30.6, 26.1 × 3, 21.1, 19.5, 18.4, 16.8, −4.5 × 2. HRMS (ESI) m/z: calcd for C32H49O2Si+, 493.3496; found, 493.3508 M + H+.

Compound 3h, yield 88%: 1H NMR (400 MHz, CDCl3): δ 8.11–8.05 (m, 1H), 7.87–7.81 (m, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.49–7.41 (m, 3H), 7.27 (s, 1H), 5.77 (d, J = 1.2 Hz, 1H), 5.40 (d, J = 5.2 Hz, 1H), 3.56–3.45 (m, 1H), 2.45–2.08 (m, 5H), 1.85–1.68 (m, 5H), 1.62–1.40 (m, 6H), 1.05 (s, 3H), 1.01 (s, 3H), 0.91 (s, 9H), 0.08 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 152.9, 142.1, 136.1, 133.9, 133.0, 129.8, 128.2, 127.1, 126.9, 125.7, 125.6, 125.5, 125.0, 121.1, 72.7, 57.7, 50.9, 49.7, 43.0, 37.5, 37.0, 35.3, 32.5, 32.2, 31.9, 31.1, 26.1 × 3, 21.0, 19.5, 18.4, 16.4, −4.4 × 2. HRMS (ESI) m/z: calcd for C35H48OSiH+, 513.3547; found, 513.3556 M + H+.

Compound 3i, yield 65%: 1H NMR (400 MHz, CDCl3): δ 8.21 (t, J = 2.0 Hz, 1H), 8.07 (dd, J = 8.4, 1.2 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 6.08 (dd, J = 3.2, 1.2 Hz, 1H), 5.39–5.33 (m, 1H), 3.56–3.40 (m, 1H), 2.36–2.15 (m, 3H), 2.13–2.00 (m, 3H), 1.87–1.36 (m, 11H), 1.08 (s, 3H), 1.07 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 152.9, 148.4, 142.1, 139.1, 132.7, 130.5, 129.2, 121.6, 121.5, 120.9, 72.7, 57.8, 50.5, 47.5, 43.0, 37.4, 36.9, 35.4, 32.2, 31.9, 31.7, 30.6, 26.1 × 3, 21.0, 19.5, 18.4, 16.8, −4.4 × 2. HRMS (ESI) m/z: calcd for C31H46NO3Si+, 508.3241; found, 508.3260 M + H+.

Compound 3j, yield 77%: 1H NMR (400 MHz, CDCl3): δ 7.38 (d, J = 8.0 Hz, 2H), 7.32–7.20 (m, 3H), 5.92 (dd, J = 2.8, 1.6 Hz, 1H), 5.38–5.35 (m, 1H), 3.55–3.45 (m, 1H), 2.35–2.14 (m, 3H), 2.13–1.99 (m, 3H), 1.86–1.41 (m, 11H), 1.07 (s, 3H), 1.06 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 154.9, 142.0, 137.5, 128.2 × 2, 127.4, 126.8 × 3, 121.1, 72.7, 57.9, 50.7, 47.4, 43.0, 37.5, 36.9, 35.5, 32.2, 31.8, 31.8, 30.6, 26.1 × 3, 21.1, 19.5, 18.4, 16.8, −4.4 × 2. HRMS (ESI) m/z: calcd for C31H47OSi+, 463.3391; found, 463.3387 M + H+.

Compound 3k, yield 76%: 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 2.4 Hz, 1H), 7.74 (td, J = 8.4, 2.4 Hz, 1H), 6.86 (dd, J = 8.4, 3.2 Hz, 1H), 5.94 (dd, J = 3.2, 1.6 Hz, 1H), 5.37–5.32 (m, 1H), 3.53–3.43 (m, 1H), 2.34–2.14 (m, 3H), 2.09–1.92 (m, 3H), 1.84–1.32 (m, 11H), 1.05 (s, 3H), 1.01 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 163.9/161.5, 150.7, 145.4/145.3, 142.0, 139.3/139.2, 131.2/131.1, 129.4, 120.9, 109.1/108.8, 72.7, 57.7, 50.5, 47.5, 43.0, 37.4, 36.9, 35.4, 32.2, 31.9, 31.7, 30.6, 26.1 × 3, 21.0, 19.5, 18.4, 16.6, −4.4 × 2. HRMS (ESI) m/z: calcd for C30H45FNOSi+, 482.3249; found, 482.3253 M + H+.

Compound 3l, yield 88%:1H NMR (400 MHz, CDCl3): δ 8.40 (d, J = 2.4 Hz, 1H), 7.64 (dd, J = 8.4, 2.4 Hz, 1H), 7.29 (d, J = 4.4 Hz, 1H), 6.03 (dd, J = 3.2, 1.6 Hz, 1H), 5.40–5.35 (m, 1H), 3.57–3.46 (m, 1H), 2.37–2.17 (m, 3H), 2.13–1.96 (m, 3H), 1.90–1.24 (m, 11H), 1.08 (s, 3H), 1.04 (s, 3H), 0.92 (s, 9H), 0.09 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 150.6, 149.6, 147.7, 142.0, 136.6, 132.0, 130.2, 123.8, 120.9, 72.7, 57.7, 50.5, 47.5, 43.0, 37.4, 36.9, 35.3, 32.2, 32.0, 31.6, 30.5, 26.1 × 3, 21.0, 19.45, 18.4, 16.7, −4.5 × 2. HRMS (ESI) m/z: calcd for C30H45ClNOSi+, 498.2953; found, 498.2963 M + H+.

Compound 3m, yield 68%: 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 8.4, 2.4 Hz, 1H), 6.69 (d, J = 8.5 Hz, 1H), 5.85 (s, 1H), 5.35 (d, J = 5.2 Hz, 1H), 3.93 (s, 3H), 3.55–3.42 (m, 1H), 2.34–2.14 (m, 3H), 2.03 (dt, J = 4.4, 3.0 Hz, 3H), 1.85–1.33 (m, 11H), 1.05 (s, 3H), 1.00 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 163.2, 151.6, 144.4, 142.1, 137.4, 127.1, 126.5, 121.0, 110.4, 72.7, 57.7, 53.5, 50.6, 47.4, 43.0, 37.4, 36.9, 35.5, 32.2, 31.8, 31.7, 30.6, 26.1 × 3, 21.0, 19.5, 18.4, 16.6, −4.5 × 2. HRMS (ESI) m/z: calcd for C31H48NO2Si+, 494.3349; found, 494.3360 M + H+.

Compound 3n, yield 75%: 1H NMR (400 MHz, CDCl3): δ 8.61 (d, J = 1.6 Hz, 1H), 8.51–8.22 (m, 1H), 7.66 (dd, J = 8.0, 1.6 Hz, 1H), 7.22 (dd, J = 8.0, 4.8 Hz, 1H), 5.99 (d, J = 1.2 Hz, 1H), 5.46–5.25 (m, 1H), 3.49 (ddd, J = 15.6, 10.8, 4.8 Hz, 1H), 2.37–2.14 (m, 3H), 2.11–1.98 (m, 3H), 1.85–1.32 (m, 11H), 1.06 (s, 3H), 1.04 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H). HRMS (ESI) m/z: calcd for C30H46NOSi+, 464.3343; found, 464.3346 M + H+. The 1H NMR data is consistent with literature.32

Compound 3o, yield 65%: 1H NMR (400 MHz, CDCl3): δ 8.49 (d, J = 6.4 Hz, 2H), 7.27–7.22 (m, 2H), 6.16 (dd, J = 3.2, 1.6 Hz, 1H), 5.37–5.32 (m, 1H), 3.53–3.43 (m, 1H), 2.33–2.15 (m, 3H), 2.15–1.99 (m, 3H), 1.84–1.40 (m, 9H), 1.10–0.99 (m, 2H, overlapped), 1.06 (s, 3H, overlapped), 1.06 (s, 3H, overlapped), 0.89 (s, 9H), 0.06 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 152.6, 149.8 × 2, 144.7, 142.1, 131.6, 121.3 × 2, 120.9, 72.7, 57.7, 50.5, 47.3, 43.0, 37.4, 36.9, 35.3, 32.2, 32.0, 31.6, 30.5, 26.1 × 3, 21.0, 19.5, 18.4, 16.7, −4.5 × 2. HRMS (ESI) m/z: calcd for C30H46NOSi+, 464.3343; found, 464.3352 M + H+.

Compound 3p, yield 66%: 1H NMR (400 MHz, CDCl3): δ 5.63 (dd, J = 2.8, 1.6 Hz, 1H), 5.35 (d, J = 5.2 Hz, 1H), 3.56–3.43 (m, 1H), 2.29 (s, 3H), 2.35–2.16 (m, 3H, overlapped), 2.16 (s, 3H), 2.13–1.98 (m, 2H), 1.83–1.46 (m, 12H), 1.03 (s, 3H), 0.89 (s, 9H), 0.82 (s, 3H), 0.06 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 165.7, 159.9, 144.4, 142.0, 132.5, 120.9, 112.5, 72.7, 56.9, 50.8, 49.5, 43.0, 37.4, 37.0, 35.4, 32.3, 32.2, 31.8, 30.9, 26.1 × 3, 20.9, 19.5, 18.4, 16.4, 12.1, 11.2, −4.5 × 2. HRMS (ESI) m/z: calcd for C30H48NO2Si+, 482.3449; found, 482.3466 M + H+.

Compound 3q, yield 78%: 1H NMR (400 MHz, CDCl3): δ 7.16–7.12 (m, 1H), 7.04 (d, J = 3.6 Hz, 1H), 6.97 (dd, J = 5.2, 3.6 Hz, 1H), 5.98 (dd, J = 2.8, 2.0 Hz, 1H), 5.38–5.33 (m, 1H), 3.57–3.42 (m, 1H), 2.38–2.15 (m, 4H), 2.03 (ddd, J = 16.0, 10.8, 3.0 Hz, 2H), 1.87–1.36 (m, 11H), 1.07 (s, 3H), 1.03 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 148.2, 142.0, 140.1, 127.3, 126.8, 123.6, 122.9, 121.0, 72.7, 57.4, 50.7, 47.8, 43.0, 37.4, 36.9, 35.6, 32.2, 31.8, 31.7, 30.6, 26.1 × 3, 21.1, 19.5, 18.4, 16.4, −4.4 × 2. HRMS (ESI) m/z: calcd for C29H45OSSi+, 469.2995; found, 469.3008 M + H+.

General Procedure for the Compounds 4a–4q

The solution of compound 3 (0.05 mmol, 1.0 equiv) and tetrabutylammonium fluoride (0.06 mmol, 1.2 equiv) in THF (10 mL) was stirred at 80 °C overnight. The mixture was neutralized with saturated NH4Cl (aq.) and the resultant mixture was extracted with EtOAc three times. The organic phase was washed with water and brine and dried over Na2SO4. The solvent was removed and the crude mixture was purified by silica gel column chromatography (EtOAc/petroleum ether, 1:4) to afford the desired compounds 4a–4q as a white solid, yield 86–95%.

Compound 4a, yield 88%: 1H NMR (400 MHz, CDCl3): δ 6.99 (s, 2H), 6.88 (s, 1H), 5.88 (dd, J = 2.8, 1.6 Hz, 1H), 5.40 (d, J = 5.1 Hz, 1H), 3.61–3.46 (m, 1H), 2.38–2.32 (m, 1H), 2.31 (s, 6H), 2.27–2.15 (m, 2H), 2.15–1.97 (m, 3H), 1.90–1.38 (m, 11H), 1.07 (s, 3H), 1.06 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 155.1, 141.2, 137.6 × 2, 137.4, 128.6, 127.0, 124.7 × 2, 121.7, 71.9, 57.8, 50.6, 47.3, 42.5, 37.3, 36.8, 35.6, 31.8, 31.7, 31.6, 30.6, 21.6 × 2, 21.1, 19.5, 16.81. HRMS (ESI) m/z: calcd for C27H37O+, 377.2839; found, 377.2822 M + H+.

Compound 4b, yield 95%: 1H NMR (400 MHz, CDCl3): δ 7.22–7.14 (m, 3H), 7.08–7.02 (m, 1H), 5.90 (dd, J = 3.2, 1.6 Hz, 1H), 5.42–5.36 (m, 1H), 3.60–3.46 (m, 1H), 2.35 (s, 3H), 2.32–2.17 (m, 3H), 2.13–1.98 (m, 3H), 1.90–1.41 (m, 11H), 1.07 (s, 3H), 1.06 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 155.0, 141.2, 137.7, 137.4, 128.1, 127.6 × 2, 127.2, 123.9, 121.6, 71.9, 57.8, 50.6, 47.3, 42.4, 37.3, 36.8, 35.5, 31.8, 31.7, 31.7, 30.6, 21.7, 21.1, 19.5, 16.8. HRMS (ESI) m/z: calcd for C26H35O+, 363.2682; found, 363.2658 M + H+.

Compound 4c, yield 94%: 1H NMR (400 MHz, CDCl3): δ 7.28 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 5.87 (dd, J = 3.2, 1.6 Hz, 1H), 5.42–5.37 (m, 1H), 3.54 (m, 1H), 2.33 (s, 3H), 2.31–2.17 (m, 3H), 2.12–1.97 (m, 3H), 1.90–1.45 (m, 11H), 1.07 (s, 3H), 1.05 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 154.6, 141.1, 136.4, 134.4, 128.8 × 2, 126.6 × 2, 126.4, 121.5, 71.8, 57.7, 50.4, 47.1, 42.3, 37.2, 36.7, 35.4, 31.7, 31.6, 31.6, 30.5, 21.1, 21.0, 19.4, 16.6. HRMS (ESI) m/z: calcd for C26H35O+, 363.2682; found, 363.2673 M + H+.

Compound 4d, yield 91%: 1H NMR (400 MHz, CDCl3): δ 7.77 (s, 2H), 7.72 (s, 1H), 6.11 (dd, J = 3.2, 2.0 Hz, 1H), 5.41–5.37 (m, 1H), 3.59–3.47 (m, 1H), 2.38–2.19 (m, 3H), 2.15–1.99 (m, 3H), 1.89–1.45 (m, 11H), 1.08 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 152.5, 141.3, 139.4, 131.7, 131.4, 131.3, 126.6, 126.6, 124.9, 122.2, 121.4, 120.4, 71.8, 57.8, 50.4, 47.5, 42.4, 37.3, 36.8, 35.3, 32.0, 31.8, 31.6, 30.5, 21.0, 19.5, 16.8. HRMS (ESI) m/z: calcd for C27H31F6O+, 485.2274; found, 485.2255 M + H+.

Compound 4e, yield 86%: 1H NMR (400 MHz, CDCl3): δ 7.36–7.28 (m, 2H), 6.98 (t, J = 8.4 Hz, 2H), 5.85 (s, 1H), 5.39 (d, J = 4.6 Hz, 1H), 3.60–3.54 (m, 1H), 2.37–2.16 (m, 3H), 2.11–1.97 (m, 3H), 1.90–1.39 (m, 11H), 1.07 (s, 3H), 1.03 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 163.1/160.7, 153.8, 141.1, 133.4, 133.4, 128.3, 128.2, 127.1, 121.5, 115.0, 114.8, 71.8, 57.6, 50.4, 47.2, 42.3, 37.2, 36.7, 35.4, 31.7, 31.6, 31.6, 30.5, 20.9, 19.4, 16.6. HRMS (ESI) m/z: calcd for C26H32F3O+, 417.2400; found, 417.2413 M + H+.

Compound 4f, yield 89%: 1H NMR (400 MHz, CDCl3): δ 7.34–7.23 (m, 4H), 5.93 (dd, J = 3.2, 1.6 Hz, 1H), 5.43–5.38 (m, 1H), 3.61–3.49 (m, 1H), 2.40–2.18 (m, 3H), 2.13–1.99 (m, 3H), 1.92–1.39 (m, 11H), 1.08 (s, 3H), 1.05 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 153.8, 141.2, 135.9, 132.6, 128.4 × 2, 128.1 × 2, 128.0, 121.6, 71.9, 57.8, 50.5, 47.3, 42.4, 37.3, 36.8, 35.4, 31.8 × 2, 31.7, 30.6, 21.0, 19.5, 16.7. HRMS (ESI) m/z: calcd for C25H32ClO+, 383.2136; found, 383.2143 M + H+.

Compound 4g, yield 89%: 1H NMR (400 MHz, CDCl3): δ 7.22 (t, J = 8.0 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.93–6.90 (m, 1H), 6.78 (dd, J = 8.0, 2.4 Hz, 1H), 5.93 (dd, J = 3.1, 1.7 Hz, 1H), 5.93 (dd, J = 3.2, 2.0 Hz, 1H), 5.41–5.37 (m, 1H), 3.81 (s, 3H), 3.46–3.59 (m, 1H), 2.37–2.18 (m, 3H), 2.13–1.97 (m, 3H), 1.88–1.46 (m, 11H), 1.07 (s, 3H), 1.05 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 159.5, 154.8, 141.3, 138.9, 129.2, 127.7, 121.6, 119.4, 112.7, 112.1, 71.9, 57.8, 55.3, 50.6, 47.4, 42.5, 37.3, 36.8, 35.6, 31.8, 31.7, 31.7, 30.6, 27.7, 21.1, 19.5, 16.8. HRMS (ESI) m/z: calcd for C26H35O2+, 379.2632; found, 379.2645 M + H+.

Compound 4h, yield 94%: 1H NMR (400 MHz, CDCl3): δ 8.10–8.05 (m, 1H), 7.86–7.80 (m, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.49–7.41 (m, 3H), 7.26 (d, J = 7.2 Hz, 1H), 5.77 (dd, J = 2.8, 1.2 Hz, 1H), 5.43 (d, J = 5.2 Hz, 1H), 3.60–3.49 (m, 1H), 2.45–2.09 (m, 5H), 1.88–1.70 (m, 6H), 1.67–1.41 (m, 7H), 1.06 (s, 3H), 1.01 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 152.8, 141.3, 136.1, 133.9, 133.0, 129.8, 128.2, 127.1, 126.9, 125.7 × 2, 125.5, 125.0, 121.6, 71.9, 57.6, 50.8, 49.7, 42.5, 37.3, 36.9, 35.2, 32.4, 31.9, 31.8, 31.1, 21.0, 19.5, 16.4. HRMS (ESI) m/z: calcd for C29H35O+, 399.2682; found, 399.2676 M + H+.

Compound 4i, yield 90%: 1H NMR (400 MHz, CDCl3): δ 8.21 (t, J = 1.6 Hz, 1H), 8.07 (dd, J = 8.0, 1.6 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 6.08 (dd, J = 3.2, 1.6 Hz, 1H), 5.42–5.37 (m, 1H), 3.60–3.46 (m, 1H), 2.39–2.19 (m, 3H), 2.14–2.01 (m, 3H), 1.91–1.35 (m, 11H), 1.08 (s, 3H), 1.07 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 152.9, 148.4, 141.3, 139.1, 132.7, 130.5, 129.1, 121.5, 121.5 × 2, 71.8, 57.8, 50.4, 47.5, 42.4, 37.3, 36.8, 35.3, 31.9, 31.8, 31.6, 30.5, 21.0, 19.5, 16.8. HRMS (ESI) m/z: calcd for C25H32NO3+, 394.2377; found, 394.2386 M + H+.

Compound 4j, yield 89%: 1H NMR (400 MHz, CDCl3): δ 7.41–7.34 (m, 2H), 7.33–7.19 (m, 3H), 5.92 (dd, J = 3.2, 1.6 Hz, 1H), 5.43–5.36 (m, 1H), 3.53 (m, 1H), 2.38–2.17 (m, 3H), 2.16–1.94 (m, 3H), 1.94–1.45 (m, 11H), 1.07 (s, 3H), 1.06 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 154.9, 141.2, 137.5, 128.2 × 2, 127.4, 126.8, 126.8 × 2, 121.6, 71.9, 57.8, 50.5, 47.3, 42.4, 37.3, 36.8, 35.5, 31.8, 31.7, 31.7, 30.6, 21.1, 19.5, 16.8. HRMS (ESI) m/z: calcd for C25H32OH+, 349.2526; found, 349.2545 M + H+.

Compound 4k, yield 94%: 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 2.0 Hz, 1H), 7.74 (td, J = 8.4, 2.4 Hz, 1H), 6.86 (dd, J = 8.4, 2.8 Hz, 1H), 5.94 (dd, J = 2.8, 1.6 Hz, 1H), 5.42–5.36 (m, 1H), 3.59–3.48 (m, 1H), 2.36–2.20 (m, 3H), 2.11–1.91 (m, 3H), 1.89–1.39 (m, 11H), 1.06 (s, 3H), 1.01 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 163.9/161.3, 150.7, 145.4/145.3, 141.3, 139.3/139.3, 131.2/131.1, 129.4, 121.4, 109.2/108.8, 71.8, 57.6, 50.5, 47.5, 42.4, 37.3, 36.8, 35.4, 31.9, 31.7, 31.6, 30.6, 21.0, 19.5, 16.6. HRMS (ESI) m/z: calcd for C24H31FNO+, 368.2384; found, 368.2398 M + H+.

Compound 4l, yield 94%: 1H NMR (400 MHz, CDCl3): δ 8.40 (d, J = 2.4 Hz, 1H), 7.63 (dd, J = 8.4, 2.4 Hz, 1H), 7.28 (d, J = 2.8 Hz, 1H), 6.03 (dd, J = 3.2, 1.6 Hz, 1H), 5.44–5.38 (m, 1H), 3.62–3.50 (m, 1H), 2.45–2.22 (m, 3H), 2.14–1.96 (m, 3H), 1.91–1.42 (m, 11H), 1.09 (s, 3H), 1.05 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 150.6, 149.6, 147.6, 141.3, 136.7, 132.2, 130.0, 123.8, 121.4, 71.8, 57.6, 50.4, 47.5, 42.4, 37.3, 36.8, 35.3, 32.0, 31.7, 31.6, 30.5, 21.0, 19.5, 16.7. HRMS (ESI) m/z: calcd for C24H30ClNOH+, 384.2089; found, 384.2103 M + H+.

Compound 4m, yield 95%: 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 8.4, 2.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 5.85 (dd, J = 2.8, 1.6 Hz, 1H), 5.42–5.35 (m, 1H), 3.92 (s, 3H), 3.58–3.47 (m, 1H), 2.26 (m, 3H), 2.10–1.97 (m, 3H), 1.88–1.36 (m, 11H), 1.06 (s, 3H), 1.01 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 163.1, 151.5, 144.4, 141.3, 137.4, 127.1, 126.4, 121.5, 110.4, 71.8, 57.6, 53.5, 50.5, 47.3, 42.4, 37.3, 36.8, 35.5, 31.7 × 2, 31.6, 30.6, 21.0, 19.5, 16.6. HRMS (ESI) m/z: calcd for C25H34NO2+, 380.2584; found, 380.2588 M + H+.

Compound 4n, yield 91%: 1H NMR (400 MHz, CDCl3): δ 8.62 (d, J = 2.0 Hz, 1H), 8.46 (dd, J = 4.8, 1.6 Hz, 1H), 7.65 (dt, J = 8.0, 2.0 Hz, 1H), 7.25–7.18 (m, 1H), 6.00 (dd, J = 3.2, 1.6 Hz, 1H), 5.42–5.36 (m, 1H), 3.61–3.48 (m, 1H), 2.39–2.20 (m, 3H), 2.06 (m, 3H), 1.90–1.39 (m, 11H), 1.07 (s, 3H), 1.05 (s, 3H). HRMS (ESI) m/z: calcd for C24H32NO+, 350.2478; found, 350.2489 M + H+. The 1H NMR data is consistent with the reported literature.33

Compound 4o, yield 94%: 1H NMR (400 MHz, CDCl3): δ 8.49 (dd, J = 4.8, 1.6 Hz, 2H), 7.28–7.23 (m, 2H), 6.17 (dd, J = 3.2, 2.0 Hz, 1H), 5.41–5.35 (m, 1H), 3.59–3.45 (m, 1H), 2.37–2.21 (m, 3H), 2.16–2.00 (m, 3H), 1.91–1.39 (m, 11H), 1.07 (s, 6H). HRMS (ESI) m/z: calcd for C24H31NOH+, 350.2478; found, 350.2489 M + H+. The 1H NMR data is consistent with the reported literature.33

Compound 4p, yield 91%: 1H NMR (400 MHz, CDCl3): δ 5.64 (d, J = 1.2 Hz, 1H), 5.38 (d, J = 4.8 Hz, 1H), 3.58–3.47 (m, 1H), 2.35–2.28 (m, 1H, overlapped), 2.29 (s, 3H), 2.28–2.25 (m, 1H), 2.15 (s, 3H), 2.10–1.97 (m, 2H), 1.90–1.77 (m, 2H), 1.76–1.19 (m, 11H), 1.04 (s, 3H), 0.82 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 165.7, 159.8, 144.3, 141.3, 132.5, 121.4, 112.5, 71.8, 56.9, 50.7, 49.5, 42.4, 37.3, 36.9, 35.4, 32.3, 31.7, 31.7, 30.9, 21.0, 19.5, 16.4, 12.0, 11.2. HRMS (ESI) m/z: calcd for C24H34NO2+, 368.2584; found, 368.2596 M + H+.

Compound 4q, yield 92%: 1H NMR (400 MHz, CDCl3): δ 7.14 (d, J = 4.8 Hz, 1H), 7.03 (d, J = 3.6 Hz, 1H), 6.97 (dd, J = 5.2, 3.6 Hz, 1H), 5.98 (dd, J = 3.2, 2.0 Hz, 1H), 5.40–5.36 (m, 1H), 3.60–3.46 (m, 1H), 2.37–2.20 (m, 3H), 2.11–1.98 (m, 3H), 1.90–1.37 (m, 11H), 1.07 (s, 3H), 1.03 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 148.2, 141.2, 140.1, 127.3, 126.8, 123.6, 122.9, 121.6, 71.9, 57.3, 50.6, 47.8, 42.5, 37.3, 36.8, 35.6, 32.3, 31.8 × 2, 31.6, 30.6, 21.1, 19.5, 16.4. HRMS (ESI) m/z: calcd for C23H31OS+, 355.2090; found, 355.2093 M + H+.

General Procedure for Compounds 6a–6r

A suspension of compound 4 (0.1 mmol, 1.0 equiv), oxazolidinecarboxylic acids 5a or 5b (0.12 mmol, 1.2 equiv), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.12 mmol, 1.2 equiv), and 4-(dimethylamino) pyridine (0.1 mmol, 1.0 equiv) in toluene (5 mL) was stirred at 80 °C for 18 h and then quenched with HCl (1 M). The mixture was added to a saturated solution of NaHCO3 (aq.) to adjust the mixture to pH 7 and then the mixture was extracted with EtOAc three times. The organic layer was treated with aqueous HCl (1 M), a saturated solution of NaHCO3 (aq.), and then brine, and each washing was performed at least three times. The organic layer was washed with 5% NaHCO3 liquid (3 × 15 mL) and dried over Na2SO4. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether, 1:15) to afford the corresponding compounds 6a–6r as a white solid, yield 46–88%.

Compound 6a, yield 82%: 1H NMR (400 MHz, CDCl3): δ 7.60–7.12 (m, 13H), 7.02 (s, 2H), 6.91 (s, 1H), 6.87 (d, J = 8.8 Hz, 2H), 5.98 (dd, J = 2.8, 1.6 Hz, 1H), 5.48 (d, J = 4.4 Hz, 1H), 5.47–5.34 (m, 1H, overlapped), 4.87 (br s, 1H), 4.84–4.73 (m, 1H), 3.85 (s, 3H), 2.42 (d, J = 8.0 Hz, 2H), 2.34 (s, 6H), 2.25 (ddd, J = 16.0, 6.4, 3.2 Hz, 1H), 2.17–1.99 (m, 3H), 1.94–1.86 (m, 2H), 1.84–1.41 (m, 9H), 1.12 (s, 3H), 1.09 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.7, 160.0, 155.0, 139.6, 137.6, 137.4, 135.8, 130.8, 130.2, 128.9, 128.8, 128.6, 128.4, 128.1, 127.2, 127.0, 124.7, 123.1, 113.6, 75.9, 57.7, 55.4, 50.4, 47.3, 38.1, 36.9, 36.9, 35.5, 31.7, 31.7, 30.6, 30.3, 27.7, 21.6 × 2, 21.0, 19.4, 16.8. HRMS (ESI) m/z: calcd for C51H56NO5+, 762.4153; found, 762.4156 M + H+.

Compound 6b, yield 85%: 1H NMR (400 MHz, CDCl3): δ 7.40–7.15 (m, 15H), 7.07–7.02 (m, 1H), 7.00–6.74 (m, 3H), 5.90 (d, J = 1.2 Hz, 1H), 5.45 (d, J = 4.4 Hz, 1H), 5.45–5.30 (m, 1H, overlapped), 4.90 (br s, 1H), 4.80–4.69 (m, 1H), 3.81 (s, 3H), 2.39 (d, J = 8.0 Hz, 2H), 2.34 (s, 3H), 2.23 (ddd, J = 15.6, 6.4, 3.2 Hz, 1H), 2.13–1.97 (m, 3H), 1.93–1.85 (m, 2H), 1.82–1.43 (m, 9H), 1.09 (s, 3H), 1.06 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.7, 160.0, 155.0, 139.6, 137.7, 137.4, 135.8, 130.7, 130.2, 128.9, 128.8, 128.4, 128.1, 128.1, 127.6, 127.2, 127.1, 123.9, 123.1, 113.6, 75.9, 57.7, 55.4, 50.4, 47.3, 38.1, 36.9, 36.9, 35.5, 31.7, 31.7, 30.6, 27.7, 21.7, 21.0, 19.4, 16.8. HRMS (ESI) m/z: calcd for C50H54NO5+, 748.3997; found, 748.3976 M + H+.

Compound 6c, yield 76%: 1H NMR (400 MHz, CDCl3): δ 7.49–7.22 (m, 14H), 7.14 (d, J = 8.0 Hz, 2H), 6.99–6.76 (m, 3H), 5.90 (dd, J = 2.8, 1.6 Hz, 1H), 5.48 (d, J = 4.4 Hz, 1H), 5.48–5.34 (m, 1H, overlapped), 4.86 (br s, 1H), 4.83–4.72 (m, 1H), 3.84 (s, 3H), 2.42 (d, J = 8.0 Hz, 2H), 2.36 (s, 3H), 2.25 (ddd, J = 15.6, 6.4, 3.2 Hz, 1H), 2.16–1.99 (m, 4H), 1.96–1.88 (m, 2H), 1.84–1.44 (m 8H), 1.11 (s, 3H), 1.08 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.7, 160.0, 154.7, 139.5, 136.5, 135.8, 134.5, 130.7, 130.2, 128.9, 128.9, 128.8, 128.7, 128.3, 128.1, 127.2, 126.7, 126.5, 123.1, 113.6, 75.9, 57.6, 55.4, 50.4, 47.2, 38.1, 36.9, 36.9, 35.5, 31.7, 31.6, 31.0, 30.5, 27.7, 21.3, 21.0, 19.4, 16.7. HRMS (ESI) m/z: calcd for C50H54NO5+, 748.3997; found, 748.3977 M + H+.

Compound 6d, yield 83%: 1H NMR (400 MHz, CDCl3): δ 7.78 (s, 2H), 7.73 (s, 1H), 7.38–7.19 (m, 12H), 6.99–6.76 (m, 3H), 6.12 (d, J = 1.2 Hz, 1H), 5.46 (d, J = 4.2 Hz, 1H), 5.46–5.31 (m, 1H, overlapped), 4.84 (br s, 1H), 4.79–4.72 (m, 1H), 3.82 (s, 3H), 2.40 (d, J = 8.0 Hz, 2H), 2.31 (ddd, J = 16.0, 6.4, 3.2 Hz, 1H), 2.14–2.01 (m, 3H), 1.93–1.86 (m, 2H), 1.84–1.46 (m, 9H), 1.10 (s, 3H), 1.09 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.7, 160.0, 152.5, 139.6, 139.4, 135.8, 131.7, 131.4, 131.3, 130.8, 130.2, 128.9, 128.8, 128.4, 128.1, 127.2, 126.6, 126.6, 124.9, 122.9, 122.2, 120.4, 120.4, 119.5, 113.6, 75.8, 57.7, 55.4, 50.3, 47.5, 38.0, 36.9, 36.9, 35.2, 31.9, 31.6, 31.6, 30.5, 27.7, 20.9, 19.4, 16.8. HRMS (ESI) m/z: calcd for C51H50F6NO5+, 870.3588; found, 870.3609 M + H+.

Compound 6e, yield 46%: 1H NMR (400 MHz, CDCl3): δ 7.44–7.17 (m, 10H), 7.27–7.17 (m, 4H), 6.97 (t, J = 8.8 Hz, 3H), 6.84 (d, J = 7.2 Hz, 2H), 5.88–5.82 (m, 1H), 5.45 (d, J = 4.4 Hz, 1H), 5.46–5.31 (m, 1H, overlapped), 4.84 (br s, 1H), 4.80–4.71 (m, 1H), 3.80 (s, 3H), 2.40 (d, J = 8.0 Hz, 2H), 2.22 (ddd, J = 15.6, 6.4, 3.2 Hz, 1H), 2.13–2.04 (m, 3H), 1.92–1.85 (m, 2H), 1.81–1.40 (m, 9H), 1.09 (s, 3H), 1.03 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.6, 163.2, 160.7, 159.9, 153.8, 139.5, 135.7, 133.4, 133.4, 130.7, 130.1, 128.8, 128.7, 128.3, 128.3, 128.2, 128.1, 127.1, 123.0, 115.1, 114.9, 113.5, 75.8, 57.6, 55.3, 50.3, 47.2, 38.0, 36.9, 36.8, 36.8, 35.3, 31.6, 31.6, 30.5, 27.7, 20.9, 19.3, 16.6. HRMS (ESI) m/z: calcd for C50H51F3NO5+, 802.3714; found, 802.3726 M + H+.

Compound 6f, yield 80%:1H NMR (400 MHz, CDCl3): δ 7.42–7.22 (m, 16H), 7.02–6.81 (m, 3H), 5.94 (dd, J = 3.2, 1.6 Hz, 1H), 5.48 (d, J = 4.0 Hz, 1H), 5.48–5.31 (m, 1H, overlapped), 4.86 (s, 1H), 4.82–4.72 (m, 1H), 3.84 (s, 3H), 2.42 (d, J = 7.6 Hz, 2H), 2.26 (ddd, J = 15.6, 6.4, 3.2 Hz, 1H), 2.16–2.00 (m, 3H), 1.95–1.87 (m, 2H), 1.84–1.73 (m, 2H), 1.73–1.42 (m, 7H), 1.11 (s, 3H), 1.07 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.7, 160.0, 153.8, 139.6, 135.8, 132.6, 130.8, 130.2, 128.9, 128.8, 128.4, 128.3, 128.1, 128.0, 128.0, 127.2, 123.0, 113.6, 75.8, 57.7, 55.4, 50.4, 47.3, 38.1, 36.9, 36.9, 36.9, 35.4, 31.7, 31.7, 30.5, 27.7, 21.0, 19.4, 16.7. HRMS (ESI) m/z: calcd for C49H51ClNO5+, 768.3450; found, 768.3469 M + H+.

Compound 6g, yield 66%: 1H NMR (400 MHz, CDCl3): δ 7.49–7.16 (m, 14H), 6.97 (d, J = 8.0 Hz, 1H), 6.93–6.91 (m, 1H), 6.85 (d, J = 7.2 Hz, 2H), 6.79 (dd, J = 8.4, 2.0 Hz, 1H), 5.93 (dd, J = 2.8, 1.6 Hz, 1H), 5.45 (d, J = 4.4 Hz, 1H), 5.46–5.31 (m, 1H, overlapped), 4.84 (s, 1 H), 4.80–4.70 (m, 1H), 3.81 (s, 3H, overlapped), 3.81 (s, 3H, overlapped), 2.39 (d, J = 7.6 Hz, 2H), 2.23 (ddd, J = 15.6, 6.4, 3.2 Hz, 1H), 2.15–1.97 (m, 3H), 1.93–1.83 (m, 2H), 1.81–1.42 (m, 9H), 1.09 (s, 3H), 1.06 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.7, 160.0, 159.4, 154.7, 139.6, 138.8, 135.8, 130.7, 130.2, 129.1, 128.9, 128.7, 128.3, 128.1, 127.6, 127.2, 126.8, 123.1, 119.4, 113.6, 112.7, 112.0, 75.8, 57.7, 55.4, 55.3, 50.4, 47.3, 38.0, 36.9, 36.9, 35.5, 31.8, 31.7, 31.7, 30.9, 27.6, 20.9, 19.3, 16.3. HRMS (ESI) m/z: calcd for C50H54NO6+, 764.3946; found, 764.3932 M + H+.

Compound 6h, yield 60%: 1H NMR (400 MHz, CDCl3): δ 8.15–8.08 (m, 1H), 7.90–7.83 (m, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.53–7.43 (m, 4H), 7.43–7.23 (m, 12H), 7.05–6.77 (m, 3H), 5.81 (d, J = 1.6 Hz, 1H), 5.52 (d, J = 4.4 Hz, 1H), 5.52–5.31 (m, 1H, overlapped), 4.88 (br s, 1H), 4.85–4.75 (m, 1H), 3.85 (s, 3H), 2.49–2.39 (m, 3H), 2.31–2.14 (m, 2H), 1.93–1.75 (m, 5H), 1.72–1.43 (m, 7H), 1.11 (s, 3H), 1.05 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.6, 159.9, 152.7, 139.5, 136.0, 135.7, 133.8, 132.9, 130.7, 130.1, 129.7, 128.8, 128.7, 128.3, 128.1, 128.0, 127.1, 127.0, 126.8, 125.6, 125.5, 125.0, 123.0, 113.5, 75.8, 57.3, 55.3, 50.5, 49.6, 38.0, 36.9, 36.8, 35.0, 32.3, 31.8, 31.8, 30.9, 27.6, 20.9, 19.3, 16.3. HRMS (ESI) m/z: calcd for C53H54NO5+, 784.3997; found, 784.4021 M + H+.

Compound 6i, yield 78%: 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 8.08 (dd, J = 8.0, 1.2 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.57–7.17 (m, 13H), 7.01–6.75 (m, 3H), 6.09 (d, J = 1.2 Hz, 1H), 5.46 (d, J = 4.0 Hz, 1H), 5.52–5.20 (m, 1H, overlapped), 4.84 (br s, 1H), 4.81–4.70 (m, 1H), 3.82 (s, 3H), 2.40 (d, J = 7.6 Hz, 2H), 2.30 (ddd, J = 15.6, 6.4, 2.4 Hz, 1H), 2.14–2.02 (m, 3H), 1.94–1.37 (m, 11H), 1.10 (s, 3H, overlapped), 1.09 (s, 3H, overlapped). 13C NMR (100 MHz, CDCl3): δ 169.7, 160.0, 152.8, 148.4, 139.6, 139.0, 135.8, 132.7, 130.7, 130.4, 130.2, 129.1, 128.9, 128.8, 128.3, 128.1, 127.2 × 4, 122.9, 121.6, 121.4, 113.6, 75.8, 57.6, 55.4, 50.3, 47.4, 38.0, 36.9, 36.9, 35.2, 31.9, 31.6, 31.6, 30.5, 27.7, 20.9, 19.4, 16.8. HRMS (ESI) m/z: calcd for C49H51N2O7+, 779.3691; found, 779.3699 M + H+.

Compound 6j, yield 80%: 1H NMR (400 MHz, CDCl3): δ 7.41–7.17 (m, 17H), 7.02–6.76 (m, 3H), 5.91 (dd, J = 2.8, 1.6 Hz, 1H), 5.45 (d, J = 4.4 Hz, 1H), 5.52–5.28 (m, 1H, overlapped), 4.84 (br s, 1H), 4.80–4.71 (m, 1H), 3.80 (s, 3H), 2.39 (d, J = 8.0 Hz, 2H), 2.23 (ddd, J = 15.6, 6.4, 3.2 Hz, 1H), 2.15–1.98 (m, 3H), 1.93–1.83 (m, 2H), 1.82–1.38 (m, 9H), 1.09 (s, 3H), 1.07 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.7, 159.9, 154.8, 139.5, 137.4, 135.7, 130.7, 130.1, 128.8, 128.7, 128.3, 128.2, 128.1, 127.3, 127.2, 126.8, 126.8, 123.0, 113.5, 75.8, 57.6, 55.3, 50.4, 47.3, 38.0, 36.9, 36.9, 35.4, 31.7, 31.7, 30.5, 27.7, 21.0, 19.4, 16.7. HRMS (ESI) m/z: calcd for C49H52NO5+, 734.3840; found, 734.3823 M + H+.

Compound 6k, yield 65%: 1H NMR (400 MHz, CDCl3): δ 8.24–8.18 (m, 1H), 7.81–7.74 (m, 2H), 7.41–7.20 (m, 12H), 6.91–6.84 (m, 3H), 5.99–5.94 (m, 1H), 5.47 (d, J = 4.0 Hz, 1H), 5.52–5.28 (m, 1H, overlapped), 4.86 (br s, 1H), 4.82–4.72 (m, 1H), 3.84 (s, 3H), 2.42 (d, J = 8.0 Hz, 2H), 2.34–2.33 (m, 2H), 2.14–2.04 (m, 3H), 1.94–1.58 (m, 10H), 1.11 (s, 3H), 1.05 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.7, 160.0, 150.6, 145.4, 145.3, 139.6, 139.3, 138.3, 135.8, 132.1, 130.2, 129.4, 128.9, 128.8, 128.8, 128.7, 128.3, 128.1, 127.2, 127.1, 127.0, 122.9, 114.4, 113.6, 109.2, 108.8, 75.8, 57.5, 55.4, 50.3, 47.4, 38.0, 36.9, 36.9, 36.9, 35.3, 31.9, 31.6, 30.5, 27.7, 20.9, 19.4, 16.6. HRMS (ESI) m/z: calcd for C48H50FN2O5+, 753.3698; found, 753.3683 M + H+.

Compound 6l, yield 57%: 1H NMR (400 MHz, CDCl3): δ 8.39 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 8.0, 2.4 Hz, 1H), 7.41–7.19 (m, 13H), 7.01–6.75 (m, 3H), 6.04–5.99 (m, 1H), 5.46 (d, J = 4.0 Hz, 1H), 5.46–5.30 (m, 1H, overlapped), 4.85 (br s, 1H), 4.81–4.71 (m, 1H), 3.82 (s, 3H), 2.40 (d, J = 7.6 Hz, 2H), 2.29 (ddd, J = 15.6, 6.4, 3.2 Hz, 1H), 2.13–1.97 (m, 4H), 1.93–1.86 (m, 2H), 1.82–1.55 (m, 7H), 1.54–1.44 (m, 1H), 1.10 (s, 3H), 1.04 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 170.0, 160.0, 150.5, 149.6, 147.6, 139.6, 136.6, 135.7, 132.0, 130.7, 130.1, 128.8, 128.7, 128.3, 128.1, 127.2, 123.8, 122.9, 113.6, 75.7, 57.5, 55.4, 50.2, 47.4, 38.0, 36.9, 36.9, 35.2, 31.9, 31.6, 30.4, 27.7, 20.9, 19.4, 16.6. HRMS (ESI) m/z: calcd for C48H50ClN2O5+, 769.3403; found, 769.3372 M + H+.

Compound 6m, yield 50%: 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 2.0 Hz, 1H), 7.61 (dd, J = 8.8, 2.4 Hz, 1H), 7.54–7.20 (m, 12H), 6.87 (d, J = 7.2 Hz, 3H), 6.72 (d, J = 8.8 Hz, 1H), 5.89 (d, J = 1.2 Hz, 1H), 5.47 (d, J = 4.4 Hz, 1H), 5.52–5.27 (m, 1H, overlapped), 4.86 (br s, 1H), 4.82–4.71 (m, 1H), 3.96 (s, 3H), 3.84 (s, 3H), 2.42 (d, J = 7.8 Hz, 2H), 2.27 (ddd, J = 15.6, 6.4, 3.2 Hz, 1H), 2.15–2.00 (m, 3H), 1.95–1.86 (m, 2H), 1.85–1.43 (m, 8H), 1.25–1.15 (m, 1H), 1.11 (s, 3H), 1.04 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.7, 163.2, 160.0, 151.5, 144.3, 139.6, 137.4, 135.8, 130.7, 130.2, 128.9, 128.7, 128.3, 128.1, 127.2, 127.1, 126.4, 123.0, 113.6, 110.4, 75.8, 57.5, 55.4, 53.5, 50.4, 47.3, 38.1, 36.9, 36.9, 35.4, 31.7, 31.7, 30.5, 27.7, 21.0, 19.4, 16.6. HRMS (ESI) m/z: calcd for C49H53FN2O6+, 765.3898; found, 765.3905 M + H+.

Compound 6n, yield 78%: 1H NMR (400 MHz, CDCl3): δ 8.64 (d, J = 2.0 Hz, 1H), 8.47 (dd, J = 4.8, 1.6 Hz, 1H), 7.44 (dt, J = 8.0, 2.0 Hz, 1H), 7.40–7.19 (m, 13H), 7.03–6.73 (m, 3H), 6.04–5.98 (m, 1H), 5.47 (d, J = 4.4 Hz, 1H), 5.47–5.31 (m, 1H, overlapped), 4.86 (br s, 1H), 4.81–4.72 (m, 1H), 3.82 (s, 3H), 2.41 (d, J = 8.0 Hz, 2H), 2.29 (ddd, J = 15.6, 6.4, 3.2 Hz, 1H), 2.15–2.03 (m, 4H), 1.95–1.86 (m, 2H), 1.85–1.47 (m, 8H), 1.11 (s, 3H), 1.07 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.7, 159.9, 151.7, 148.0, 148.0, 139.5, 135.7, 133.8, 133.0, 130.7, 130.1, 129.3, 128.8, 128.7, 128.3, 128.1, 127.2, 123.1, 122.9, 113.5, 75.7, 57.5, 55.3, 50.3, 47.4, 38.0, 36.9, 36.8, 35.2, 31.9, 31.6, 30.4, 27.7, 20.9, 19.3, 16.7. HRMS (ESI) m/z: calcd for C48H51N2O5+, 735.3792; found, 735.3802 M + H+.

Compound 6o, yield 56%: 1H NMR (400 MHz, CDCl3): δ 8.51 (dd, J = 4.8, 1.6 Hz, 2H), 7.40–7.20 (m, 15H), 6.85 (d, J = 7.2 Hz, 2H), 6.20–6.16 (m, 1H), 5.45 (d, J = 4.4 Hz, 1H), 5.50–5.32 (m, 1H, overlapped), 4.84 (br s, 1H), 4.80–4.71 (m, 1H), 3.82 (s, 3H), 2.40 (d, J = 7.6 Hz, 2H), 2.28 (ddd, J = 16.0, 6.4, 3.2 Hz, 1H), 2.19–2.04 (m, 3H), 1.93–1.85 (m, 2H), 1.85–1.45 (m, 9H), 1.10 (s, 3H), 1.08 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.7, 160.0, 152.6, 149.8, 144.6, 139.6, 135.8, 131.6, 130.8, 130.2, 128.9, 128.7, 128.3, 128.1, 127.2, 122.9, 121.3, 113.6, 75.8, 57.6, 55.4, 50.3, 47.2, 38.0, 36.9, 36.9, 35.2, 31.9, 31.6, 31.6, 30.4, 27.7, 20.9, 19.4, 16.7. HRMS (ESI) m/z: calcd for C48H51N2O5+, 735.3792; found, 753.3802 M + H+.

Compound 6p, yield 66%: 1H NMR (400 MHz, CDCl3): δ 7.53–7.08 (m, 12H), 6.99–6.74 (m, 3H), 5.65 (d, J = 1.6 Hz, 1H), 5.45 (d, J = 4.4 Hz, 1H), 5.49–5.30 (m, 1H, overlapped), 4.84 (br s, 1H), 4.81–4.70 (m, 1H), 3.81 (s, 3H), 2.39 (d, J = 7.6 Hz, 2H), 2.33–2.24 (m, 1H, overlapped), 2.30 (s, 3H, overlapped), 2.17 (s, 3H), 2.14–1.99 (m, 3H), 1.88 (d, J = 10.8 Hz, 2H), 1.80–1.35 (m, 9H), 1.07 (s, 3H), 0.83 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.6, 165.6, 159.9, 159.7, 144.2, 139.5, 135.7, 132.4, 130.7, 130.1, 128.8, 128.7, 128.3, 128.1, 127.1, 122.9, 113.5, 112.4, 75.7, 56.7, 55.3, 50.5, 49.4, 38.0, 36.9, 36.9 × 2, 35.3, 32.2, 31.6, 30.8, 27.6, 20.8, 19.3, 16.4, 12.0, 11.2. HRMS (ESI) m/z: calcd for C48H53N2O6+, 753.3898; found, 753.3907 M + H+.

Compound 6q, yield 46%: 1H NMR (400 MHz, CDCl3): δ 7.56–7.07 (m, 14H), 7.04 (d, J = 3.6 Hz, 1H), 6.97 (dd, J = 5.2, 3.6 Hz, 1H), 6.85 (d, J = 7.2 Hz, 2H), 6.05–5.95 (m, 1H), 5.44 (d, J = 4.4 Hz, 1H), 5.48–5.28 (m, 1H, overlapped), 4.84 (br s, 1H), 4.80–4.70 (m, 1H), 3.82 (s, 3H), 2.39 (d, J = 7.2 Hz, 2H), 2.30–2.19 (m, 2H), 2.13–1.96 (m, 2H), 1.94–1.86 (m, 2H), 1.81–1.51 (m, 8H), 1.22–1.20 (m, 1H), 1.09 (s, 3H), 1.04 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.7, 160.0, 148.1, 140.1, 139.6, 135.8, 130.8, 130.2, 128.9, 128.8, 128.4, 128.1, 127.3, 127.2, 126.8, 124.5, 123.6, 123.0, 122.9, 113.6, 75.8, 57.2, 55.4, 50.4, 47.7, 38.1, 36.9, 36.9, 35.5, 31.7, 31.6, 30.5, 30.3, 27.7, 21.1, 19.4, 16.4. HRMS (ESI) m/z: calcd for C47H50NO5S+, 740.9785; found, 740.9802 M + H+.

Compound 6r, yield 60%: 1H NMR (400 MHz, CDCl3): δ 7.52–7.12 (m, 12H), 6.91 (d, J = 8.7 Hz, 2H), 6.53–6.19 (m, 1H), 5.91 (dd, J = 3.2, 1.6 Hz, 1H), 5.41 (br s, 1H), 5.32 (s, 1H), 4.52 (d, J = 3.6 Hz, 2H), 3.81 (s, 3H), 2.22 (ddd, J = 15.6, 6.4, 3.2 Hz, 1H), 2.12–1.97 (m, 4H), 1.89–1.39 (m, 11H), 1.18–1.12 (m, 1H), 1.08 (s, 9H), 1.05 (s, 3H), 1.00 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 160.3, 154.8, 139.8, 137.4, 128.8, 128.5, 128.2, 128.0, 127.3, 126.9, 126.8, 126.5, 122.6, 113.8, 92.0, 80.8, 75.6, 57.7, 55.4, 50.4, 47.3, 36.9, 36.8, 35.4, 31.7, 31.7, 30.5, 28.0 × 3, 22.8, 21.0, 19.3, 16.7. HRMS (ESI) m/z: calcd for C47H56NO6+, 730.4102; found, 730.4121 M + H+.

General Procedure for the Compounds 7a–7r

The ester compound 6 (0.05 mmol 1.0 equiv) was added to MeOH (2 mL) and treated with 4-toluene sulfonyl chloride (0.3 mmol, 6.0 equiv). The reaction mixture was stirred at room temperature for 6 h and then diluted with EtOAc. The organic layer was washed with a saturated solution of NaHCO3 (aq.) and brine, dried with Na2SO4, filtered, and concentrated. The crude mixture was purified by silica gel column chromatography (EtOAc/petroleum ether, 1:12) to afford the desired hybrids 7a–7r as a white solid, yield 60–85%.

Compound 7a, yield 60%: 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 7.6 Hz, 2H), 7.55–7.29 (m, 8H), 7.08 (d, J = 9.2 Hz, 1H), 7.00 (s, 2H), 6.89 (s, 1H), 5.88 (s, 1H), 5.79 (d, J = 9.2 Hz, 1H), 5.44 (d, J = 4.4 Hz 1H), 4.83–4.70 (m, 1H), 4.62 (s, 1H), 3.47 (br s, 1H), 2.51–2.40 (m, 1H), 2.49–2.33 (m, 1H), 2.31 (s, 6H), 2.21 (ddd, J = 15.6, 6.4, 3.2 Hz, 1H), 2.13–2.01 (m, 3H), 1.89–1.52 (m, 10H), 1.48–1.42 (m, 1H), 1.09 (s, 3H), 1.06 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 172.5, 166.9, 155.0, 139.7, 138.9, 137.6 × 2, 137.3, 134.4, 131.8, 128.8 × 3, 128.7, 128.6, 128.0, 127.2 × 2, 127.0 × 2, 126.9, 124.7 × 2, 123.0, 76.8, 73.5, 57.7, 54.8, 50.4, 47.3, 38.1, 36.9 × 2, 35.5, 31.7, 31.7, 30.5, 27.6, 21.5 × 2, 21.0, 19.3, 16.8. HRMS (ESI) m/z: calcd for C43H50NO4+, 644.3734; found, 644.3753 M + H+.

Compound 7b, yield 84%: 1H NMR (400 MHz, CDCl3): δ 7.80–7.72 (d, J = 7.2 Hz, 2H), 7.54–7.39 (m, 5H), 7.36 (t, J = 7.6 Hz, 2H), 7.32–7.26 (m, 1H), 7.22–7.13 (m, 3H), 7.08–7.01 (m, 2H), 5.88 (d, J = 1.2 Hz, 1H), 5.77 (dd, J = 9.2, 1.6 Hz, 1H), 5.42 (d, J = 4.8 Hz, 1H), 4.79–4.68 (m, 1H), 4.61 (s, 1H), 3.37 (br s, 1H), 2.51–2.40 (m, 1H), 2.39–2.32 (m, 1H), 2.34 (s, 3H), 2.21 (ddd, J = 15.6, 6.4, 3.2 Hz, 1H), 2.12–2.00 (m, 3H), 1.90–1.46 (m, 10H), 1.46–1.40 (m, 1H), 1.08 (s, 3H), 1.05 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 172.5, 166.9, 155.0, 139.8, 138.9, 137.7, 137.3, 134.4, 131.9, 128.8, 128.8 × 2, 128.8 × 2, 128.1, 128.0, 127.6, 127.2 × 2, 127.1, 127.0 × 2, 123.9, 123.0, 76.9, 73.5, 57.7, 54.8, 50.4, 47.3, 38.1, 36.9 × 2, 35.5, 31.7, 31.7, 30.6, 27.6, 21.7, 21.0, 19.4, 16.8. HRMS (ESI) m/z: calcd for C42H48NO4+, 630.3578; found, 630.3538 M + H+.

Compound 7c, yield 81%: 1H NMR (600 MHz, CDCl3): δ 7.76 (d, J = 7.2 Hz, 2H), 7.50 (t, J = 7.2 Hz, 1H), 7.47–7.40 (m, 4H), 7.36 (t, J = 7.2 Hz, 2H), 7.32–7.24 (m, 3H), 7.09 (d, J = 7.8 Hz, 2H), 7.01 (d, J = 9.0 Hz, 1H), 5.86 (d, J = 0.6 Hz, 1H), 5.76 (dd, J = 9.0, 1.2 Hz, 1H), 5.44–5.39 (m, 1H), 4.77–4.70 (m, 1H), 4.61 (s, 1H), 3.34 (br s, 1H), 2.47–2.41 (m, 1H), 2.37–2.34 (m, 1H), 2.33 (s, 3H), 2.20 (ddd, J = 15.6, 6.4, 3.2 Hz, 1H), 2.09–1.98 (m, 3H), 1.87–1.80 (m, 2H), 1.79–1.71 (m, 1H), 1.71–1.50 (m, 6H), 1.48–1.41 (m, 1H), 1.14–1.09 (m, 1H), 1.08 (s, 3H), 1.04 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 172.5, 166.9, 154.7, 139.7, 138.9, 136.5, 134.5, 134.4, 131.9, 129.0 × 2, 128.8 × 2, 128.8 × 2, 128.0, 127.2 × 2, 127.0 × 2, 126.7 × 2, 126.5, 123.0, 76.9, 73.5, 57.7, 54.8, 50.4, 47.2, 38.1, 36.9 × 2, 35.5, 31.7, 31.7, 30.5, 27.6, 21.3, 21.0, 19.4, 16.7. HRMS (ESI) m/z: calcd for C42H48NO4+, 630.3578; found, 630.3538 M + H+.

Compound 7d, yield 65%: 1H NMR (400 MHz, CDCl3): δ 7.80–7.70 (m, 5H), 7.50–7.39 (m, 5H), 7.38–7.33 (m, 2H), 7.32–7.26 (m, 1H), 7.06 (d, J = 9.2 Hz, 1H), 6.10 (s, 1H), 5.78 (dd, J = 9.2, 1.6 Hz, 1H), 5.42 (d, J = 4.8 Hz, 1H), 4.80–4.68 (m, 1H), 4.61 (s, 1H), 3.45 (br s, 1H), 2.50–2.40 (m, 1H), 2.40–2.33 (m, 1H), 2.29 (ddd, J = 15.6, 6.4, 3.2 Hz, 1H), 2.13–1.99 (m, 3H), 1.89–1.54 (m, 10H), 1.53–1.46 (m, 1H), 1.08 (s, 3H), 1.07 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 172.5, 166.9, 152.5, 139.8, 139.4, 138.9, 134.4, 131.8, 131.7, 131.4, 131.3, 128.8 × 2, 128.8 × 2, 128.0, 127.2 × 2, 127.0 × 2, 126.6, 126.6, 124.9, 122.7, 122.2, 120.4, 76.7, 73.5, 57.7, 54.8, 50.3, 47.5, 38.1, 36.9 × 2, 35.2, 31.9, 31.6, 30.4, 27.5, 20.9, 19.4, 16.8. HRMS (ESI) m/z: calcd for C43H44F6NO4+, 752.3169; found, 752.3142 M + H+.

Compound 7e, yield 84%: 1H NMR (400 MHz, CDCl3): δ 7.79–7.72 (d, J = 7.2 Hz, 2H), 7.53 (m, 3H), 7.46 (m, 6H), 7.39–7.33 (m, 2H), 7.32–7.26 (m, 1H), 7.02 (d, J = 9.2 Hz, 1H), 6.01 (d, J = 1.2 Hz, 1H), 5.78 (dd, J = 9.2, 1.6 Hz, 1H), 5.42 (d, J = 4.8 Hz, 1H), 4.80–4.69 (m, 1H), 4.62 (d, J = 2.0 Hz, 1H), 3.35 (br s, 1H), 2.50–2.40 (m, 1H), 2.39–2.32 (m, 1H), 2.25 (ddd, J = 15.6, 6.4, 3.2 Hz, 1H), 2.11–2.01 (m, 3H), 1.88–1.52 (m, 10H), 1.50–1.42 (m, 1H), 1.08 (s, 3H), 1.06 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 172.5, 166.9, 153.8, 141.0, 141.0, 139.8, 138.9, 134.4, 131.9 × 2, 129.7, 128.8 × 2, 128.8 × 2, 128.0, 127.2 × 2, 127.0 × 2, 126.9 × 2, 125.2, 125.2, 122.9, 76.8, 73.5, 57.7, 54.8, 50.4, 47.4, 38.1, 36.9 × 2, 35.3, 31.9, 31.6, 30.5, 27.6, 20.9, 19.4, 16.8. HRMS (ESI) m/z: calcd for C42H45F3NO4+, 684.3295; found, 684.3287 M + H+.

Compound 7f, yield 77%: 1H NMR (600 MHz, CDCl3): δ 7.76 (d, J = 7.2 Hz, 2H), 7.51 (t, J = 7.2 Hz, 1H), 7.47–7.44 (m, 3H), 7.37 (t, J = 7.2 Hz, 2H), 7.32–7.23 (m, 6H, overlapped), 6.99 (d, J = 9.0 Hz, 1H), 5.90 (s, 1H), 5.78 (d, J = 9.0 Hz, 1H), 5.44–5.41 (m, 1H), 4.78–4.71 (m, 1H), 4.63–4.61 (m, 1H), 3.28 (d, J = 3.0 Hz, 1H), 2.49–2.41 (m, 1H), 2.38–2.32 (m, 1H), 2.25–2.20 (m, 1H), 2.06–1.99 (m, 3H), 1.88–1.80 (m, 2H), 1.79–1.58 (m, 7H), 1.47–1.40 (m, 1H), 1.15–1.09 (m, 1H), 1.08 (s, 3H), 1.03 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 172.5, 166.9, 153.8, 139.8, 138.9, 135.9, 134.4, 132.6, 131.9, 128.9 × 2, 128.8 × 2, 128.4 × 2, 128.1 × 2, 128.0, 128.0, 127.2 × 2, 127.0 × 2, 123.0, 76.9, 73.5, 57.7, 54.8, 50.4, 47.3, 38.1, 36.9 × 2, 35.4, 31.8, 31.7, 30.5, 27.6, 21.0, 19.4, 16.7. HRMS (ESI) m/z: calcd for C41H45ClNO4+, 650.3032; found, 650.3013 M + H+.

Compound 7g, yield 62%: 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 7.2 Hz, 2H), 7.54–7.39 (m, 5H), 7.36 (t, J = 7.2 Hz, 2H), 7.32–7.26 (m, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 9.2 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.91 (s, 1H), 6.78 (dd, J = 8.0, 2.4 Hz, 1H), 5.92 (s, 1H), 5.84–5.72 (dd, J = 9.2, 1.6 Hz, 1H), 5.42 (d, J = 4.8 Hz, 1H), 4.80–4.67 (m, 1H), 4.61 (s, 1H), 3.80 (s, 3H), 3.40 (br s, 1H), 2.50–2.39 (m, 1H), 2.39–2.30 (m, 1H), 2.26–2.15 (m, 1H), 2.13–1.96 (m, 3H), 1.88–1.78 (m, 2H), 1.78–1.43 (m, 8H), 1.43–1.32 (m, 1H), 1.07 (s, 3H), 1.05 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 172.5, 166.9, 159.4, 154.7, 139.7, 138.9, 138.8, 134.4, 131.8, 129.1, 128.8 × 2, 128.8 × 2, 128.0, 127.6, 127.2 × 2, 127.0 × 2, 123.0, 119.4, 112.7, 112.0, 76.8, 73.5, 57.7, 55.3, 54.8, 50.4, 47.3, 38.1, 36.9 × 2, 35.4, 31.7 × 2, 30.5, 27.6, 21.0, 19.4, 16.8. HRMS (ESI) m/z: calcd for C42H48NO5+, 646.3527; found, 646.3546 M + H+.

Compound 7h, yield 70%: 1H NMR (400 MHz, CDCl3): δ 8.10–8.04 (m, 1H), 7.85–7.78 (m, 1H), 7.78–7.72 (m, 3H), 7.53–7.39 (m, 8H), 7.39–7.31 (m, 2H), 7.31–7.25 (m, 2H), 7.08 (d, J = 9.2 Hz, 1H), 5.81–5.73 (m, 2H), 5.45 (d, J = 4.8 Hz, 1H), 4.81–4.67 (m, 1H), 4.61 (dd, J = 3.2, 2.4 Hz, 1H), 3.48 (d, J = 3.6 Hz, 1H), 2.51–2.34 (m, 3H), 2.27–2.07 (m, 2H), 1.89–1.39 (m, 11H), 1.14–1.09 (m, 1H), 1.06 (s, 3H), 1.00 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 172.5, 166.9, 152.8, 139.8, 138.9, 136.0, 134.3, 133.8, 132.9, 131.8, 129.7, 128.8 × 2, 128.8 × 2, 128.2, 127.9, 127.2 × 2, 127.1, 127.0 × 2, 126.8, 125.6 × 2, 125.5, 125.0, 123.0, 76.8, 73.5, 57.5, 54.8, 50.6, 49.6, 38.1, 36.9, 36.9, 35.1, 32.4, 31.9, 31.0, 27.5, 21.9, 19.4, 16.4. HRMS (ESI) m/z: calcd for C45H48NO4+, 666.3578; found, 666.3617 M + H+.

Compound 7i, yield 75%: 1H NMR (600 MHz, CDCl3): δ 8.23 (t, J = 1.8 Hz, 1H), 8.07 (ddd, J = 7.8, 2.4, 0.6 Hz, 1H), 7.79 (m, 2H), 7.67 (dt, J = 7.8, 1.2 Hz, 1H), 7.53–7.29 (m, 1H), 7.47–7.42 (m, 5H), 7.38–7.35 (m, 2H), 7.30 (t, J = 7.2 Hz, 1H), 7.00 (d, J = 9.0 Hz, 1H), 6.07 (dd, J = 3.6, 1.8 Hz, 1H), 5.80 (dd, J = 9.6, 2.4 Hz, 1H), 5.44–5.41 (m, 1H), 4.78–4.71 (m, 1H), 4.62 (d, J = 1.8 Hz, 1H), 3.32 (s, 1H), 2.50–2.40 (m, 1H), 2.37 (ddd, J = 13.2, 5.4, 2.4 Hz, 1H), 2.28 (ddd, J = 16.2, 6.6, 3.6 Hz, 1H), 2.12–2.04 (m, 3H), 1.88–1.81 (m, 2H), 1.78 (qd, J = 10.8, 4.8 Hz, 1H), 1.72–1.55 (m, 7H), 1.48 (td, J = 12.0, 5.4 Hz, 1H), 1.09 (s, 3H), 1.08 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 172.5, 166.9, 152.9, 148.4, 139.8, 139.0, 138.9, 134.4, 132.7, 131.9, 130.4, 129.1, 128.8 × 2, 128.8 × 2, 128.0, 127.2 × 2, 127.0 × 2, 122.8, 121.6, 121.5, 76.8, 73.5, 57.7, 54.8, 50.3, 47.4, 38.1, 36.9 × 2, 35.3, 31.9, 31.6, 30.5, 27.6, 20.9, 19.4, 16.8. HRMS (ESI) m/z: calcd for C41H45N2O6+, 661.3272; found, 661.3248 M + H+.

Compound 7j, yield 86%: 1H NMR (600 MHz, CDCl3): δ 7.78–7.73 (m, 2H), 7.51 (t, J = 7.2 Hz, 1H), 7.48–7.41 (m, 4H), 7.39–7.34 (m, 4H), 7.33–7.27 (m, 3H), 7.22 (t, J = 7.2 Hz, 1H), 7.01 (d, J = 9.6 Hz, 1H), 5.91 (dd, J = 3.0, 1.8 Hz, 1H), 5.78 (dd, J = 9.6, 1.8 Hz, 1H), 5.45–5.39 (m, 1H), 4.79–4.71 (m, 1H), 4.62 (s, 1H), 3.31 (d, J = 3.0 Hz, 1H), 2.49–2.41 (m, 1H), 2.37 (ddd, J = 12.6, 4.8, 1.8 Hz, 1H), 2.22 (ddd, J = 15.6, 6.6, 3.0 Hz, 1H), 2.11–2.02 (m, 3H), 1.88–1.81 (m, 2H), 1.77 (qd, J = 10.8, 4.8 Hz, 1H), 1.72–1.53 (m, 7H), 1.47 (td, J = 12.0, 6.0 Hz, 1H), 1.09 (s, 3H), 1.06 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 172.5, 166.9, 154.9, 139.8, 138.9, 137.4, 134.4, 131.9, 128.8 × 2, 128.8 × 2, 128.2 × 2, 128.0, 127.3, 127.2 × 2, 127.0 × 2, 126.9, 126.8 × 2, 123.0, 77.0, 73.5, 57.7, 54.8, 50.4, 47.3, 38.1, 36.9 × 2, 35.4, 31.7, 31.7, 30.6, 27.6, 21.0, 19.4, 16.8. HRMS (ESI) m/z: calcd for C41H46NO4+, 616.3421; found, 616.3444 M + H+.

Compound 7k, yield 69%: 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 2.0 Hz, 1H), 7.81–7.69 (m, 3H), 7.53–7.28 (m, 8H), 7.06 (d, J = 9.2 Hz, 1H), 6.86 (dd, J = 8.4, 2.8 Hz, 1H), 5.94 (s, 1H), 5.77 (dd, J = 9.2, 1.6 Hz, 1H), 5.42 (d, J = 4.8 Hz, 1H), 4.80–4.67 (m, 1H), 4.61 (dd, J = 2.8, 2.4 Hz, 1H), 3.48 (d, J = 3.6 Hz, 1H), 2.50–2.40 (m, 1H), 2.39–2.32 (m, 1H), 2.26 (ddd, J = 15.6, 6.4, 3.2 Hz, 1H), 2.07–1.93 (m, 3H), 1.89–1.50 (m, 10H), 1.48–1.40 (td, J = 12.0, 5.2 Hz, 1H), 1.08 (s, 3H), 1.01 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 172.5, 166.9, 163.8/161.5, 150.6, 145.4/145.3, 139.8, 139.3/139.2, 138.9, 134.4, 131.8, 131.1/131.0, 129.3, 128.8 × 2, 128.8 × 2, 128.0, 127.2 × 2, 127.0 × 2, 122.8, 109.2/108.8, 76.7, 73.5, 57.5, 54.8, 50.3, 47.4, 38.1, 36.9 × 2, 35.3, 31.8, 31.6, 30.5, 27.5, 20.9, 19.4, 16.6. HRMS (ESI) m/z: calcd for C40H44FN2O4+, 635.3280; found, 635.3283 M + H+.

Compound 7l, yield 66%: 1H NMR (400 MHz, CDCl3): δ 8.37 (d, J = 2.4 Hz, 1H), 7.79–7.73 (m, 2H), 7.62–7.57 (m, 1H), 7.53–7.40 (m, 5H), 7.39–7.33 (m, 2H), 7.32–7.24 (m, 2H), 7.02 (d, J = 9.2 Hz, 1H), 6.03–5.97 (m, 1H), 5.78 (dd, J = 9.2, 2.0 Hz, 1H), 5.44–5.40 (m, 1H), 4.79–4.69 (m, 1H), 4.62 (s, 1H), 3.37 (s, 1H), 2.49–2.39 (m, 1H), 2.39–2.32 (m, 1H), 2.29–2.22 (m, 1H), 2.02 (m, 3H), 1.89–1.79 (m, 2H), 1.79–1.56 (m, 8H), 1.49–1.41 (m, 1H), 1.08 (s, 3H), 1.02 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 172.5, 166.9, 150.6, 149.6, 147.7, 139.8, 138.9, 136.7, 134.4, 132.0, 131.9, 130.1, 128.8 × 2, 128.8 × 2, 128.0, 127.2 × 2, 127.0 × 2, 123.8, 122.8, 76.8, 73.5, 57.5, 54.8, 50.3, 47.5, 38.1, 36.9 × 2, 35.2, 32.0, 31.6, 30.5, 27.5, 20.9, 19.4, 16.7. HRMS (ESI) m/z: calcd for C40H44ClN2O4+, 651.2984; found, 651.3030 M + H+.

Compound 7m, yield 75%: 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 2.4 Hz, 1H), 7.80–7.71 (m, 2H), 7.57 (dd, J = 8.8, 2.4 Hz, 1H), 7.53–7.40 (m, 5H), 7.37 (t, J = 7.2 Hz, 2H), 7.33–7.27 (m, 1H), 7.02 (d, J = 9.2 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 5.85 (dd J = 2.8, 1.6 Hz, 1H), 5.77 (dd, J = 9.6, 2.0 Hz, 1H), 5.42 (d, J = 5.2 Hz, 1H), 4.79–4.68 (m, 1H), 4.61 (s, 1H), 3.93 (s, 3H), 3.35 (br s, 1H), 2.50–2.39 (m, 1H), 2.39–2.30 (m, 1H), 2.22 (ddd, J = 15.6, 6.4, 3.2 Hz, 1H), 2.10–1.98 (m, 3H), 1.88–1.79 (m, 2H), 1.78–1.52 (m, 8H), 1.51–1.43 (m, 1H), 1.08 (s, 3H), 1.00 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 172.5, 166.9, 163.2, 151.5, 144.4, 139.8, 138.9, 137.4, 134.4, 131.9, 128.8 × 2, 128.8 × 2, 128.0, 127.2 × 2, 127.1, 127.0 × 2, 126.4, 122.9, 110.4, 76.8, 73.5, 57.5, 54.8, 53.5, 50.4, 47.3, 38.1, 36.9 × 2, 35.4, 31.7, 31.7, 30.5, 27.6, 21.0, 19.4, 16.6. HRMS (ESI) m/z: calcd for C41H47N2O5+, 647.3479; found, 647.3480 M + H+.

Compound 7n, yield 76%: 1H NMR (600 MHz, CDCl3): δ 8.60 (s, 1H), 8.44 (d, J = 3.6 Hz, 1H), 7.76 (d, J = 7.2 Hz, 2H), 7.64 (d, J = 8.4 Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.47–7.41 (m, 4H), 7.36 (t, J = 7.8 Hz, 2H), 7.30 (t, J = 7.8 Hz, 1H), 7.22 (dd, J = 7.8, 5.4 Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H), 5.99 (s, 1H), 5.77 (dd, J = 9.0, 1.2 Hz, 1H), 5.44–5.40 (m, 1H), 4.78–4.70 (m, 1H), 4.62 (d, J = 1.8 Hz, 1H), 2.48–2.41 (m, 1H), 2.36 (ddd, J = 13.2, 4.8, 1.2 Hz, 1H), 2.26 (ddd, J = 15.6, 6.6, 3.6 Hz, 1H), 2.09–2.00 (m, 3H), 1.87–1.81 (m, 2H), 1.76 (qd, J = 9.0, 1.2 Hz, 1H), 1.71–1.53 (m, 7H), 1.47 (dt, J = 12.0, 5.4 Hz, 1H), 1.08 (s, 3H), 1.03 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 172.5, 166.9, 151.7, 148.0, 147.9, 139.8, 139.0, 134.4, 133.9, 133.1, 131.8, 129.4, 128.8 × 2, 128.8 × 2, 128.0, 127.2 × 2, 127.0 × 2, 123.2, 122.9, 76.7, 73.5, 57.6, 54.9, 50.3, 47.5, 38.1, 36.9 × 2, 35.3, 31.9, 31.7, 30.5, 27.6, 20.9, 19.4, 16.7. HRMS (ESI) m/z: calcd for C40H45N2O4+, 617.3374; found, 617.3398 M + H+.

Compound 7o, yield 84%: 1H NMR (600 MHz, CDCl3): δ 8.48 (d, J = 6.0 Hz, 2H), 7.78–7.71 (m, 2H), 7.51 (t, J = 7.2 Hz, 1H), 7.48–7.41 (m, 4H), 7.37 (t, J = 7.2 Hz, 2H), 7.30 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 6.6 Hz, 2H), 7.02 (d, J = 9.6 Hz, 1H), 6.16 (dd, J = 3.0, 1.8 Hz, 1H), 5.77 (dd, J = 9.6, 1.8 Hz, 1H), 5.44–5.40 (m, 1H), 4.77–4.71 (m, 1H), 4.62 (d, J = 2.4 Hz, 1H), 2.48–2.40 (m, 1H), 2.36 (ddd, J = 13.2, 4.8, 1.2 Hz, 1H), 2.26 (ddd, J = 13.2, 5.4, 1.8 Hz, 1H), 2.13–2.03 (m, 3H), 1.87–1.80 (m, 2H), 1.76 (qd, J = 10.8, 5.4, 1H), 1.71–1.61 (m, 5H), 1.61–1.53 (m, 2H), 1.48–1.41 (m, 1H), 1.09 (s, 3H), 1.07 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 172.5, 166.9, 152.6, 149.8 × 2, 144.7, 139.8, 138.9, 134.4, 131.9, 131.6, 128.8 × 2, 128.8 × 2, 128.0, 127.2 × 2, 127.0 × 2, 122.8, 121.3 × 2, 76.7, 73.5, 57.6, 54.8, 50.3, 47.2, 38.1, 36.9 × 2, 35.2, 31.9, 31.6, 30.4, 27.6, 20.9, 19.4, 16.7. HRMS (ESI) m/z: calcd for C40H45N2O4+, 617.3374; found, 617.3348 M + H+.

Compound 7p, yield 72%: 1H NMR (400 MHz, CDCl3): δ 7.79–7.72 (m, 2H), 7.53–7.38 (m, 5H), 7.35 (t, J = 7.2 Hz, 2H), 7.32–7.25 (m, 1H) 7.07 (dd, J = 9.2, 3.6 Hz, 1H), 5.79–5.73 (m, 1H), 5.64 (d, J = 1.6 Hz, 1H), 5.42 (d, J = 5.2 Hz, 1H), 4.79–4.68 (m, 1H), 4.61 (s, 1H), 3.49 (br s, 1H), 2.49–2.39 (m, 1H), 2.39–2.31 (m, 1H), 2.31–2.20 (m, 1H, overlapped), 2.29 (s, 3H, overlapped), 2.15 (s, 3H), 2.10–1.98 (m, 3H), 1.88–1.75 (m, 3H), 1.74–1.62 (m, 3H), 1.62–1.34 (m, 5H), 1.06 (s, 3H), 0.82 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 172.5, 166.9, 165.7, 159.8, 144.3, 139.8, 138.9, 134.4, 132.4, 131.8, 128.8 × 2, 128.8 × 2, 127.9, 127.2 × 2, 127.0 × 2, 122.8, 112.4, 76.7, 73.5, 56.8, 54.8, 50.6, 49.4, 38.1, 36.9, 36.9, 35.3, 32.2, 31.7, 30.8, 27.5, 20.8, 19.4, 16.4, 12.0, 11.2. HRMS (ESI) m/z: calcd for C40H47N2O5+, 635.3479; found, 635.3438 M + H+.

Compound 7q, yield 78%: 1H NMR (400 MHz, CDCl3): δ 7.79–7.72 (m, 2H), 7.53–7.39 (m, 5H), 7.36 (t, J = 7.2 Hz, 2H), 7.32–7.26 (m, 1H), 7.13 (d, J = 5.2 Hz, 1H), 7.07–7.00 (m, 2H), 6.96 (dd, J = 5.2, 3.6 Hz, 1H), 5.97 (dd, J = 5.2, 2.0 Hz, 1H), 5.41 (d, J = 5.2 Hz, 1H), 4.79–4.68 (m, 1H), 4.61 (s, 1H), 3.39 (s, 1H), 2.49–2.39 (m, 1H), 2.39–2.31 (m, 1H), 2.27–2.17 (m, 2H), 2.09–1.96 (m, 2H), 1.91–1.77 (m, 2H), 1.77–1.46 (m, 8H), 1.16–1.05 (m, 1H, overlapped), 1.08 (s, 3H), 1.02 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 172.5, 166.9, 148.1, 140.1, 139.7, 138.9, 134.4, 131.9, 128.8 × 2, 128.8 × 2, 128.0, 127.3, 127.2 × 2, 127.0 × 2, 126.7, 123.6, 122.9 × 2, 76.8, 73.5, 57.2, 54.8, 50.4, 47.7, 38.1, 36.9 × 2, 35.5, 31.7, 31.6, 30.5, 27.6, 21.0, 19.4, 16.4. HRMS (ESI) m/z: calcd for C39H44NO4S+, 622.2986; found, 622.2986 M + H+.

Compound 7r, yield 68%: 1H NMR (400 MHz, CDCl3): δ 7.41–7.19 (m, 10H), 5.91 (s, 1H), 5.51–5.37 (m, 2H), 5.25 (d, J = 9.2 Hz, 1H), 4.80–4.67 (m, 1H), 4.45 (s, 1H), 3.22 (br s, 1H), 2.45–2.41 (m, 1H), 2.41–2.31 (m, 1H), 2.23 (ddd, J = 15.6, 6.4, 3.2 Hz, 1H), 2.14–1.99 (m, 3H), 1.97–1.81 (m, 2H), 1.81–1.53 (m, 8H), 1.53–1.46 (m, 1H), 1.40 (s, 9H), 1.10 (s, 3H), 1.06 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 172.5, 155.1, 154.9, 139.8, 139.6, 137.4, 128.72, 128.2 × 2, 127.8, 127.3, 126.9, 126.8 × 2, 126.8, 126.8, 123.0, 79.9, 76.7, 73.8, 57.7, 56.0, 50.5, 47.3, 38.1, 37.0, 36.9 × 2, 35.5, 31.7, 30.6, 28.4 × 3, 27.5, 21.0, 19.4, 16.8. HRMS (ESI) m/z: calcd for C39H50NO5+, 612.3684; found, 612.3702 M + H+.

Biology

Materials

MTT (M2128) was purchased from Sigma-Aldrich (St. Louis, Mo, USA). The HepG-2 cells were purchased from American Type Culture Collection (ATCC, Manassas, VA, USA). Cells were cultured in Dulbecco’s modified Eagle’s medium with 10% fetal bovine serum and incubated with 5% CO2.

MTT Assay

MTT assay was employed primarily for determination. The in vitro inhibitory activities of eighteen hybrids on HepG-2 cells were evaluated. HepG-2 cells were seeded at a density of 5 × 103/well in a 96-well plate for 24 h and then treated with different concentrations of compounds dissolved in 100% dimethyl sulfoxide (DMSO) for 24 h, with the final DMSO concentrations lower than 0.1%. Control cells were treated with Taxol containing 0.1% DMSO. DMSO served as a negative control. Then, 10 μL of MTT (5 mg/mL) was added into each well and incubated for another 4 h. The purple formazan crystals were dissolved in 100 μL of DMSO and the absorbance was detected at 570 nm using a microplate reader (Thermo MK3, USA).

Acknowledgments

We are grateful for the financial support for this work from the NSFC (31570341 and 31870329).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c00558.

  • 1H and 13C NMR spectra for all the new compounds (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao0c00558_si_001.pdf (16.8MB, pdf)

References

  1. Wani M. C.; Taylor H. L.; Wall M. E.; Coggon P.; McPhail A. T. Plant antitumor agents. VI. isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J. Am. Chem. Soc. 1971, 93, 2325–2327. 10.1021/ja00738a045. [DOI] [PubMed] [Google Scholar]
  2. Ojima I.; Wang X.; Jing Y.; Wang C. Quest for efficacious next-generation taxoid anticancer agents and their tumor-targeted delivery. J. Nat. Prod. 2018, 81, 703–721. 10.1021/acs.jnatprod.7b01012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Schiff P. B.; Fant J.; Horwitz S. B. Promotion of microtubule assembly in vitro by taxol. Nature 1979, 277, 665–667. 10.1038/277665a0. [DOI] [PubMed] [Google Scholar]
  4. Schiff P. B.; Horwitz S. B. Taxol stabilizes microtubules in mouse fibroblast cells. Proc. Natl. Acad. Sci. U.S.A. 1980, 77, 1561–1565. 10.1073/pnas.77.3.1561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Xiao H.; Verdier-Pinard P.; Fernandez-Fuentes N.; Burd B.; Angeletti R.; Fiser A.; Horwitz S. B.; Orr G. A. Insights into the mechanism of microtubule stabilization by Taxol. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 10166–10173. 10.1073/pnas.0603704103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ojima I.; Das M. Recent advances in the chemistry and biology of new generation taxoids. J. Nat. Prod. 2009, 72, 554–565. 10.1021/np8006556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Kingston D. G. I. Recent advances in the chemistry of taxol. J. Nat. Prod. 2000, 63, 726–734. 10.1021/np000064n. [DOI] [PubMed] [Google Scholar]
  8. Chen X.-X.; Gao F.; Wang Q.; Huang X.; Wang D. Design, synthesis and biological evaluation of paclitaxel-mimics possessing only the oxetane D-ring and side chain structures. Fitoterapia 2014, 92, 111–115. 10.1016/j.fitote.2013.10.015. [DOI] [PubMed] [Google Scholar]
  9. Gueritte F. General and recent aspects of the chemistry and structure-activity relationships of taxoids. Curr. Pharm. Des. 2001, 7, 1229–1249. 10.2174/1381612013397429. [DOI] [PubMed] [Google Scholar]
  10. Lataste H.; Senilh V.; Wright M.; Guenard D.; Potier P. Relationships between the structures of taxol and baccatine III derivatives and their in vitro action on the disassembly of mammalian brain and Physarum amoebal microtubules. Proc. Natl. Acad. Sci. U.S.A. 1984, 81, 4090–4094. 10.1073/pnas.81.13.4090. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Parness J.; Kingston D. G. I.; Powell R. G.; Harracksingh C.; Horwitz S. B. Structure-activity study of cytotoxicity and microtubule assembly in vitro by taxol and related taxanes. Biochem. Biophys. Res. Commun. 1982, 105, 1082–1089. 10.1016/0006-291x(82)91080-4. [DOI] [PubMed] [Google Scholar]
  12. Fang W.-S.; Liang X.-T. Recent progress in structure activity relationship and mechanistic studies of taxol analogues. Mini-Rev. Med. Chem. 2005, 5, 1–12. 10.2174/1389557053402837. [DOI] [PubMed] [Google Scholar]
  13. Almqvist F.; Manner S.; Thornqvist V.; Berg U.; Wallin M.; Frejd T. r. Spirobicyclo 2.2.2 octane derivatives: mimetics of baccatin III and paclitaxel (Taxol). Org. Biomol. Chem. 2004, 2, 3085–3090. 10.1039/b409678a. [DOI] [PubMed] [Google Scholar]
  14. Howarth J.; Kenny P.; McDonnell S.; O’Connor A. The design and synthesis of guanosine compounds with in vitro activity against the colon cancer cell line SW480: Non-taxane derived mimics of taxol. Bioorg. Med. Chem. Lett. 2003, 13, 2693–2697. 10.1016/s0960-894x(03)00543-2. [DOI] [PubMed] [Google Scholar]
  15. Manner S.; Oltner V. T.; Oredsson S.; Ellervik U.; Frejd T. Spiro-bicyclo 2.2.2 octane derivatives as paclitaxel mimetics. Synthesis and toxicity evaluation in breast cancer cell lines. Org. Biomol. Chem. 2013, 11, 7134–7144. 10.1039/c3ob41417e. [DOI] [PubMed] [Google Scholar]
  16. Roussi F.; Ngo Q. A.; Thoret S.; Guéritte F.; Guénard D. The design and synthesis of new steroidal compounds as potential mimics of toxoids. Eur. J. Org. Chem. 2005, 2005, 3952–3961. 10.1002/ejoc.200500203. [DOI] [Google Scholar]
  17. Zefirova O. N.; Nurieva E. V.; Lemcke H.; Ivanov A. A.; Shishov D. V.; Weiss D. G.; Kuznetsov S. A.; Zefirov N. S. Design, synthesis, and bioactivity of putative tubulin ligands with adamantane core. Bioorg. Med. Chem. Lett. 2008, 18, 5091–5094. 10.1016/j.bmcl.2008.07.116. [DOI] [PubMed] [Google Scholar]
  18. Kar A. K.; Braun P. D.; Wandless T. J. Synthesis and evaluation of daunorubicin-paclitaxel dimers. Bioorg. Med. Chem. Lett. 2000, 10, 261–264. 10.1016/s0960-894x(99)00667-8. [DOI] [PubMed] [Google Scholar]
  19. Liu C.; Strobl J. S.; Bane S.; Schilling J. K.; McCracken M.; Chatterjee S. K.; Rahim-Bata R.; Kingston D. G. I. Design, synthesis, and bioactivities of steroid-linked Taxol analogues as potential targeted drugs for prostate and breast cancer. J. Nat. Prod. 2004, 67, 152–159. 10.1021/np030296x. [DOI] [PubMed] [Google Scholar]
  20. Sahu P.; Gidwani B.; Dhongade H. J. Pharmacological activities of dehydroepiandrosterone: A review. Steroids 2020, 153, 108507. 10.1016/j.steroids.2019.108507. [DOI] [PubMed] [Google Scholar]
  21. de Bono J. S.; Logothetis C. J.; Haqq C. M.; Scher H. I. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 2011, 364, 1995–2005. 10.1056/NEJMoa1014618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Chen Y.; Coussanes G.; Souris C.; Aillard P.; Kaldre D.; Runggatscher K.; Kubicek S.; Di Mauro G.; Maryasin B.; Maulide N. A domino 10-Step total synthesis of FR252921 and its analogues, complex macrocyclic immunosuppressants. J. Am. Chem. Soc. 2019, 141, 13772–13777. 10.1021/jacs.9b07185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Fuwa H.; Ebine M.; Sasaki M. Total synthesis of the proposed structure of brevenal. J. Am. Chem. Soc. 2006, 128, 9648–9650. 10.1021/ja062524q. [DOI] [PubMed] [Google Scholar]
  24. Schnabel C.; Hiersemann M. Total synthesis of jatrophane diterpenes from euphorbia characias. Org. Lett. 2009, 11, 2555–2558. 10.1021/ol900819u. [DOI] [PubMed] [Google Scholar]
  25. Schmidt B.; Krehl S.; Kelling A.; Schilde U. Synthesis of 8-Aryl-Substituted coumarins based on ring-closing metathesis and Suzuki-Miyaura coupling: Synthesis of a furyl coumarin natural Product from Galipea panamensis. J. Org. Chem. 2012, 77, 2360–2367. 10.1021/jo2026564. [DOI] [PubMed] [Google Scholar]
  26. Schacht M.; Boehlich G. J.; de Vries J.; Bertram S.; Gabriel G.; Zimmermann P.; Heisig P.; Schützenmeister N. Protecting-group-free total syntheses of rubrolide R and S. Eur. J. Org. Chem. 2017, 2017, 1745–1748. 10.1002/ejoc.201700158. [DOI] [Google Scholar]
  27. Bharti R.; Bal Reddy C.; Kumar S.; Das P. Supported palladium nanoparticle-catalysed Suzuki-Miyaura cross-coupling approach for synthesis of aminoarylbenzosuberene analogues from natural precursor. Appl. Organomet. Chem. 2017, 31, e3749 10.1002/aoc.3749. [DOI] [Google Scholar]
  28. Ruszkowska J.; Chrobak R.; Zero P.; Maurin J. K.; Szawkało J.; Czarnocki Z. The Suzuki-Miyaura reaction in the chemical transformations of vindoline. Acta Biochim. Pol. 2007, 54, 857–861. 10.18388/abp.2007_3188. [DOI] [PubMed] [Google Scholar]
  29. The oxazolidinecarboxylic acids 5a and 5b were purchased from Yunnan Hongdou Pharmaceutical Co., Ltd, China.
  30. Deng G.; Zhou B.; Wang J.; Chen Z.; Gong L.; Gong Y.; Wu D.; Li Y.; Zhang H.; Yang X. Synthesis and antitumor activity of novel steroidal imidazolium salt derivatives. Eur. J. Med. Chem. 2019, 168, 232–252. 10.1016/j.ejmech.2019.02.025. [DOI] [PubMed] [Google Scholar]
  31. Yu W.; Jin Z. A facile generation of enolates from silyl enol ethers by potassium ethoxide. Tetrahedron Lett. 2001, 42, 369–372. 10.1016/s0040-4039(00)01970-5. [DOI] [Google Scholar]
  32. Armstrong R. J.; Niwetmarin W.; Aggarwal V. K. Synthesis of Functionalized Alkenes by a Transition-Metal-Free Zweifel Coupling. Org. Lett. 2017, 19, 2762–2765. 10.1021/acs.orglett.7b01124. [DOI] [PubMed] [Google Scholar]
  33. Potter G. A.; Barrie S. E.; Jarman M.; Rowlands M. G. Novel steroidal inhibitors of human cytochrome P450(17-Alpha) (17-Alpha-Hydroxylase-C-17,C-20-Lyase)-potential agents for the treatment of prostatic-cancer. J. Med. Chem. 1995, 38, 2463–2471. 10.1021/jm00013a022. [DOI] [PubMed] [Google Scholar]

Associated Data

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Supplementary Materials

ao0c00558_si_001.pdf (16.8MB, pdf)

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