4.1. Chemistry
The key chemical reactant oseltamivir phosphate and the other chemicals and reagents were purchased from commercial suppliers and used without further purification. Solvents were of reagent grade and were purified and dried with standard methods when necessary. Thin-layer chromatography (TLC) was performed on Silica Gel GF254 for TLC, and spots were visualized by irradiation with UV light (λ = 254 nm and 365 nm). Flash column chromatography was carried out on columns packed with Silica Gel 60 (200–300 mesh), purchased from Qingdao Haiyang Chemical Company. A rotary evaporator was used for the concentration of the reaction solutions under reduced pressure. All melting points (mp) were determined on a micro melting-point apparatus (RY-1G; Tianjin TianGuang Optical Instruments) and were uncorrected. The 1H NMR and 13C NMR spectra were recorded on a Bruker AV-400 spectrometer in the indicated solvent DMSO-d6 and CD3OD with tetramethylsilane (TMS) as the internal standard. Chemical shifts were expressed in δ units (ppm) and J values were presented in hertz (Hz). Mass spectra (MS) were obtained on an API 4000 LC/MS spectrometer (Applied Biosystems, Foster City, CA, USA).
4.1.1. General Procedure for the Preparation of Compounds 1a–18a
A solution of 4-hydroxybenzaldehyde (1 g, 8.2 mmol), substituted benzyl bromide (8.4 mmol, 1.02 eq) and potassium carbonate (1.7 g, 12.3 mmol) in 30 mL of
N,N-dimethylformamide (DMF) was stirred overnight under an inert atmosphere at room temperature [
29]. Subsequently, 50 mL water was added and the mixture was extracted with ethyl acetate (40 mL × 3). The combined organic phase was washed with a saturated brine (30 mL × 2), dried over anhydrous MgSO
4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (10–50% ethyl acetate in petroleum ether) to obtain the corresponding products,
1a–
18a.
(2-((4-Formylphenoxy)methyl)phenyl)boronic acid (1a). White powder, 31%, mp: 185.1–186.7 °C. 1H NMR (400 MHz, DMSO-d6) δ: 9.83 (s, J = 27.6 Hz, 1H, CHO), 8.10 (s, 1H, OH), 7.93–7.51 (m, 3H, 3Ph-H), 7.51–6.98 (m, 5H, 5Ph-H), 5.58 (d, J = 15.7 Hz, 1H, CH), 5.36 (s, 1H, CH), 3.42 (s, 1H, OH).
(3-((4-Formylphenoxy)methyl)phenyl)boronic acid (2a). White powder, 24%, mp: 170.1–172.2 °C. 1H NMR (400 MHz, DMSO-d6) δ: 9.96–9.76 (m, J = 4.2 Hz, 1H, CHO), 8.09 (s, 1H, OH), 7.98–7.63 (m, 4H, 4Ph-H), 7.50 (d, J = 7.3 Hz, 1H, Ph-H), 7.39 (dt, J = 21.4, 6.6 Hz, 1H, Ph-H), 7.22 (dd, J = 6.6, 1.8 Hz, 2H, 2Ph-H), 5.22 (t, J = 24.0 Hz, 2H, CH2), 3.52 (s, 1H, OH).
(4-((4-Formylphenoxy)methyl)phenyl)boronic acid (3a). White powder, 38%, mp: 129.5–131.7 °C. 1H NMR (400 MHz, DMSO-d6) δ: 9.87 (s, 1H, CHO), 7.87 (d, J = 8.1 Hz, 2H, 2Ph-H), 7.81 (d, J = 7.5 Hz, 2H, 2Ph-H), 7.42 (d, J = 7.5 Hz, 2H, 2Ph-H), 7.21 (d, J = 8.2 Hz, 2H, 2Ph-H), 5.24 (s, 2H, CH2), 2.89 (s, 1H, OH), 2.73 (s, 1H, OH).
Methyl 2-((4-formylphenoxy)methyl)benzoate (4a). White powder, 62%, mp: 89.8–91.8 °C. 1H NMR (400 MHz, DMSO-d6) δ: 9.88 (s, 1H, CHO), 7.94 (d, J = 7.7 Hz, 1H, Ph-H), 7.89 (d, J = 8.7 Hz, 2H, 2Ph-H), 7.69–7.61 (m, 2H, 2Ph-H), 7.54–7.47 (m, 1H, Ph-H), 7.19 (d, J = 8.7 Hz, 2H, 2Ph-H), 5.54 (s, 2H, CH2), 3.81 (s, 3H, CH3).
Methyl 3-((4-formylphenoxy)methyl)benzoate (5a). White powder, 64%, mp: 79.1–81.2 °C. 1H NMR (400 MHz, DMSO-d6) δ: 9.88 (s, 1H, CHO), 8.07 (s, 1H, Ph-H), 7.95 (d, J = 7.8 Hz, 1H, Ph-H), 7.89 (d, J = 8.7 Hz, 2H, 2Ph-H), 7.76 (d, J = 7.7 Hz, 1H, Ph-H), 7.58 (t, J = 7.7 Hz, 1H, Ph-H), 7.23 (d, J = 8.6 Hz, 2H, 2Ph-H), 5.33 (s, 2H, CH2), 3.87 (s, 3H, CH3).
Methyl 4-((4-formylphenoxy)methyl)benzoate (6a). White powder, 61%, mp: 107.1–109.5 °C. 1H NMR (400 MHz, DMSO-d6) δ: 9.88 (s, 1H, CHO), 8.00 (d, J = 8.2 Hz, 2H, 2Ph-H), 7.89 (d, J = 8.7 Hz, 2H, 2Ph-H), 7.62 (d, J = 8.1 Hz, 2H, 2Ph-H), 7.23 (d, J = 8.6 Hz, 2H, 2Ph-H), 5.35 (s, 2H, CH2), 3.86 (s, 3H, CH3).
Methyl 3-((4-formylphenoxy)methyl)-4-methoxybenzoate (7a). White powder, 76%, mp: 66.5–68.1 °C. 1H NMR (400 MHz, DMSO-d6) δ: 9.89 (s, 1H, CHO), 8.06–7.97 (m, 2H, 2Ph-H), 7.89 (d, J = 8.6 Hz, 2H, 2Ph-H), 7.22 (d, J = 8.5 Hz, 3H, 3Ph-H), 5.23 (s, 2H, CH2), 3.93 (s, 3H, CH3), 3.82 (s, 3H, CH3).
Methyl 3-chloro-4-((4-formylphenoxy)methyl)benzoate (8a). White powder, 73%, mp: 109.8–111.5 °C. 1H NMR (400 MHz, DMSO-d6) δ: 9.90 (s, 1H, CHO), 8.01 (d, J = 1.2 Hz, 1H, Ph-H), 7.97 (dd, J = 8.0, 1.3 Hz, 1H, Ph-H), 7.91 (d, J = 8.7 Hz, 2H, 2Ph-H), 7.78 (d, J = 8.0 Hz, 1H, Ph-H), 7.26 (d, J = 8.7 Hz, 2H, 2Ph-H), 5.37 (s, 2H, CH2), 3.89 (s, 3H, CH3).
Methyl 4-((4-formylphenoxy)methyl)-3-methoxybenzoate (9a). White powder, 72%, mp: 92.2–93.8 °C. 1H NMR (400 MHz, DMSO-d6) δ: 9.88 (s, 1H, CHO), 7.89 (d, J = 8.7 Hz, 2H, 2Ph-H), 7.64–7.53 (m, J = 19.5, 6.1 Hz, 3H, 3Ph-H), 7.21 (d, J = 8.6 Hz, 2H, 2Ph-H), 5.26 (s, 2H, CH2), 3.92 (s, 3H, CH3), 3.87 (s, 3H, CH3).
Methyl 4-((4-formylphenoxy)methyl)-2-methoxybenzoate (10a). White powder, 72%, mp: 79.1–81.5 °C. 1H NMR (400 MHz, DMSO-d6) δ: 9.88 (s, 1H, CHO), 7.89 (d, J = 8.7 Hz, 2H, 2Ph-H), 7.68 (d, J = 7.9 Hz, 1H, Ph-H), 7.27 (s, 1H, Ph-H), 7.23 (d, J = 8.6 Hz, 2H, 2Ph-H), 7.11 (d, J = 7.9 Hz, 1H, Ph-H), 5.29 (s, 2H, CH2), 3.84 (s, 3H, CH3), 3.79 (s, 3H, CH3).
4-((2-Nitrobenzyl)oxy)benzaldehyde (11a). White powder, 62%, mp: 85.1–87.2 °C. 1H NMR (400 MHz, DMSO-d6) δ: 9.88 (s, 1H, CHO), 8.15 (d, J = 8.1 Hz, 1H, Ph-H), 7.92–7.87 (m, 2H, 2Ph-H), 7.84–7.77 (m, 2H, 2Ph-H), 7.65 (ddd, J = 8.6, 6.8, 4.1 Hz, 1H, Ph-H), 7.22 (d, J = 8.7 Hz, 2H, 2Ph-H), 5.59 (s, 2H, CH2).
4-((3-Nitrobenzyl)oxy)benzaldehyde (12a). White powder, 66%, mp: 79.7–81.5 °C. 1H NMR (400 MHz, DMSO-d6) δ: 9.89 (s, 1H, CHO), 8.35 (s, 1H, Ph-H), 8.22 (dd, J = 8.2, 1.4 Hz, 1H, Ph-H), 7.92 (dd, J = 17.7, 8.2 Hz, 3H, 3Ph-H), 7.73 (t, J = 7.9 Hz, 1H, Ph-H), 7.26 (d, J = 8.7 Hz, 2H, 2Ph-H), 5.41 (s, 2H, CH2).
4-((4-Nitrobenzyl)oxy)benzaldehyde (13a). Yellow powder, 65%. 1H NMR (400 MHz, DMSO-d6) δ: 9.89 (s, 1H, CHO), 8.28 (d, J = 8.7 Hz, 2H, 2Ph-H), 7.90 (d, J = 8.7 Hz, 2H, 2Ph-H), 7.75 (d, J = 8.6 Hz, 2H, 2Ph-H), 7.24 (d, J = 8.7 Hz, 2H, 2Ph-H), 5.42 (s, 2H, CH2).
3-((4-Formylphenoxy)methyl)benzamide (14a). Pale yellow oil, 63% yield. 1H NMR (400 MHz, DMSO-d6) δ: 9.87 (s, 1H, CHO), 8.00 (d, J = 12.9 Hz, 2H, 2Ph-H), 7.87 (dd, J = 11.6, 8.6 Hz, 3H, Ph-H, NH2), 7.62 (d, J = 7.6 Hz, 1H, Ph-H), 7.49 (t, J = 7.7 Hz, 1H, Ph-H), 7.41 (s, 1H, Ph-H), 7.23 (d, J = 8.6 Hz, 2H, 2Ph-H), 5.28 (s, 2H, CH2).
4-((4-Formylphenoxy)methyl)benzamide (15a). White powder, 73%, mp: 185.8–188.2 °C. 1H NMR (400 MHz, DMSO-d6) δ: 9.88 (s, 1H, CHO), 7.99 (s, 1H, NH), 7.89 (t, J = 7.8 Hz, 4H, 4Ph-H), 7.54 (d, J = 8.1 Hz, 2H, 2Ph-H), 7.39 (s, 1H, NH), 7.22 (d, J = 8.7 Hz, 2H, 2Ph-H), 5.31 (s, 2H, CH2).
3-((4-Formylphenoxy)methyl)benzenesulfonamide (16a). White powder, 67%, mp: 137.2–139.7 °C. 1H NMR (400 MHz, DMSO-d6) δ: 9.89 (s, 1H, CHO), 7.95 (s, 1H, Ph-H), 7.90 (d, J = 8.8 Hz, 2H, 2Ph-H), 7.82 (d, J = 7.8 Hz, 1H, Ph-H), 7.70 (d, J = 7.7 Hz, 1H, Ph-H), 7.62 (t, J = 7.7 Hz, 1H, Ph-H), 7.42 (s, 2H, NH2), 7.24 (d, J = 8.7 Hz, 2H, 2Ph-H), 5.34 (s, 2H, CH2).
4-((4-Formylphenoxy)methyl)benzenesulfonamide (17a). White powder, 65%, mp: 124.5–126.5 °C. 1H NMR (400 MHz, DMSO-d6) δ: 9.87 (s, 1H, CHO), 7.87 (dd, J = 12.4, 8.5 Hz, 4H, 4Ph-H), 7.65 (d, J = 8.2 Hz, 2H, 2Ph-H), 7.37 (s, 2H, NH2), 7.22 (d, J = 8.6 Hz, 2H, 2Ph-H), 5.34 (s, 2H, CH2).
4-((4-Formylphenoxy)methyl)benzenesulfonyl fluoride (18a). White powder, 72%, mp: 74.8–76.2 °C. 1H NMR (400 MHz, DMSO-d6) δ: 9.89 (s, 1H, CHO), 8.19 (d, J = 8.4 Hz, 2H, 2Ph-H), 7.89 (dd, J = 16.0, 8.4 Hz, 4H, 4Ph-H), 7.25 (d, J = 8.6 Hz, 2H, 2Ph-H), 5.47 (s, 2H, CH2).
4.1.2. General Procedure for the Preparation of Compounds 1b–18b
To a solution of oseltamivir phosphate (0.82 g, 2.0 mmol) in 30 mL methanol, different substituted aldehyde (2.0 mmol, 1 eq) was added at room temperature. The reaction mixture was stirred for 0.5 h, and then NaBH3CN (0.31 g, 5.0 mmol, 2.5 eq) was added. The resulting mixture was stirred at room temperature until completion, monitored by TLC. After removal of the excess solvent under reduced pressure, saturated brine (30 mL) and saturated sodium carbonate solution (10 mL) were added. The aqueous phase was extracted with ethyl acetate (3 × 30 mL). Then, the combined organic phase was dried over anhydrous MgSO4, filtered, and purified by flash column chromatography (0–6% methanol in dichloromethane) to provide the corresponding intermediate 1b–18b.
(2-((4-((((1S,5R,6R)-6-acetamido-3-(ethoxycarbonyl)-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)methyl)phenoxy)methyl)phenyl)boronic acid (1b). Pale yellow powder, 74% yield, mp: 132.5–134.7 °C. 1H NMR (400 MHz, CD3OD) δ: 7.44–7.21 (m, 6H, 6Ph-H), 6.99 (d, J = 7.9 Hz, 2H, 2Ph-H), 6.78 (s, 1H, CH), 5.10 (s, 2H, CH2), 4.21 (q, J = 7.0 Hz, 2H, CH2), 4.07 (d, J = 10.3 Hz, 1H, CH), 3.93 (t, J = 9.4 Hz, 1H, CH), 3.86 (d, J = 12.7 Hz, 1H, CH), 3.70 (d, J = 12.6 Hz, 1H, CH), 3.42–3.36 (m, 1H, CH), 2.95 (td, J = 10.0, 5.4 Hz, 1H, CH), 2.83 (dd, J = 17.7, 5.0 Hz, 1H, CH), 2.34–2.20 (m, 1H, CH), 2.00 (s, 3H, CH3), 1.59–1.42 (m, 4H, 2CH2), 1.29 (t, J = 7.0 Hz, 3H, CH3), 0.90 (q, J = 8.0 Hz, 6H, 2CH3). ESI-MS: m/z 553.3 [M + H]+, C30H41BN2O7 (552.48).
(3-((4-((((1S,5R,6R)-6-acetamido-3-(ethoxycarbonyl)-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)methyl)phenoxy)methyl)phenyl)boronic acid (2b). White powder, 73% yield, mp: 163.1–165.2 °C. 1H NMR (400 MHz, CD3OD) δ: 7.84–7.70 (m, 1H, Ph-H), 7.70–7.57 (m, 1H, Ph-H), 7.45 (d, J = 7.4 Hz, 1H, Ph-H), 7.33 (t, J = 7.5 Hz, 1H, Ph-H), 7.25 (d, J = 7.8 Hz, 2H, 2Ph-H), 6.97 (d, J = 7.7 Hz, 2H, 2Ph-H), 6.78 (s, 1H, CH), 5.07 (s, 2H, CH2), 4.22 (q, J = 6.9 Hz, 2H, CH2), 4.07 (d, J = 8.5 Hz, 1H, CH), 3.94 (t, J = 9.5 Hz, 1H, CH), 3.88 (d, J = 12.6 Hz, 1H, CH), 3.71 (d, J = 12.7 Hz, 1H, CH), 3.39 (q, J = 5.1 Hz, 1H, CH), 2.99 (dt, J = 15.1, 7.8 Hz, 1H, CH), 2.84 (dd, J = 17.5, 5.0 Hz, 1H, CH), 2.35–2.23 (m, 1H, CH), 1.99 (s, 3H, CH3), 1.57–1.44 (m, 4H, 2CH2), 1.29 (t, J = 6.9 Hz, 3H, CH3), 0.89 (q, J = 8.0 Hz, 6H, 2CH3). ESI-MS: m/z 553.5 [M + H]+, C30H41BN2O7 (552.48).
(4-((4-((((1S,5R,6R)-6-acetamido-3-(ethoxycarbonyl)-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)methyl)phenoxy)methyl)phenyl)boronic acid (3b). White powder, 69% yield, mp: 189.2–191.1 °C. 1H NMR (400 MHz, CD3OD) δ: 7.70 (s, 2H, 2Ph-H), 7.39 (d, J = 7.5 Hz, 2H, 2Ph-H), 7.25 (d, J = 7.9 Hz, 2H, 2Ph-H), 6.96 (d, J = 7.9 Hz, 2H, 2Ph-H), 6.79 (s, 1H, CH), 5.08 (s, 2H, CH2), 4.22 (q, J = 7.0 Hz, 2H, CH2), 4.08 (d, J = 7.9 Hz, 1H, CH), 4.00–3.85 (m, 2H, 2CH), 3.73 (d, J = 12.7 Hz, 1H, CH), 3.42–3.36 (m, 1H, CH), 3.00 (dt, J = 15.1, 7.7 Hz, 1H, CH), 2.84 (dd, J = 17.4, 5.0 Hz, 1H, CH), 2.30 (dd, J = 17.4, 9.9 Hz, 1H, CH), 2.00 (s, 3H, CH3), 1.59–1.42 (m, 4H, 2CH2), 1.29 (t, J = 7.0 Hz, 3H, CH3), 0.89 (q, J = 8.0 Hz, 6H, 2CH3). ESI-MS: m/z 553.4 [M + H]+, C30H41BN2O7 (552.48).
Methyl 2-((4-((((1S,5R,6R)-6-acetamido-3-(ethoxycarbonyl)-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)methyl)phenoxy)methyl)benzoate (4b). White powder, 68% yield, mp: 72.7–74.1 °C. 1H NMR (400 MHz, CD3OD) δ: 7.97 (d, J = 7.8 Hz, 1H, Ph-H), 7.69 (d, J = 7.8 Hz, 1H, Ph-H), 7.56 (t, J = 7.6 Hz, 1H, Ph-H), 7.41 (t, J = 7.6 Hz, 1H, Ph-H), 7.24 (d, J = 8.5 Hz, 2H, 2Ph-H), 6.93 (d, J = 8.6 Hz, 2H, 2Ph-H), 6.77 (s, 1H, CH), 5.43 (s, 2H, CH2), 4.21 (q, J = 7.1 Hz, 2H, CH2), 4.05 (d, J = 8.5 Hz, 1H, CH), 3.94–3.85 (m, 4H, CH, CH3), 3.80 (d, J = 12.7 Hz, 1H, CH), 3.64 (d, J = 12.7 Hz, 1H, CH), 3.37 (dt, J = 11.2, 5.6 Hz, 1H, CH), 2.94–2.85 (m, 1H, CH), 2.81 (dd, J = 17.6, 5.0 Hz, 1H, CH), 2.28–2.18 (m, 1H, CH), 1.99 (s, 3H, CH3), 1.56–1.45 (m, 4H, 2CH2), 1.29 (t, J = 7.1 Hz, 3H, CH3), 0.89 (dt, J = 9.9, 7.4 Hz, 6H, 2CH3). ESI-MS: m/z 567.6 [M + H]+, C32H42N2O7 (566.70).
Methyl 3-((4-((((1S,5R,6R)-6-acetamido-3-(ethoxycarbonyl)-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)methyl)phenoxy)methyl)benzoate (5b). White powder, 72% yield, mp: 75.2–77.1 °C. 1H NMR (400 MHz, CD3OD) δ: 8.09 (s, 1H, Ph-H), 7.96 (d, J = 7.8 Hz, 1H, Ph-H), 7.68 (d, J = 7.6 Hz, 1H, Ph-H), 7.49 (t, J = 7.7 Hz, 1H, Ph-H), 7.25 (d, J = 8.5 Hz, 2H, 2Ph-H), 6.97 (d, J = 8.5 Hz, 2H, 2Ph-H), 6.78 (s, 1H, CH), 5.13 (s, 2H, CH2), 4.21 (q, J = 7.1 Hz, 2H, CH2), 4.06 (d, J = 8.2 Hz, 1H, CH), 3.97–3.87 (m, 4H, CH, CH3), 3.84 (d, J = 12.7 Hz, 1H, CH), 3.67 (d, J = 12.7 Hz, 1H, CH), 3.41–3.34 (m, 1H, CH), 2.93 (d, J = 5.5 Hz, 1H, CH), 2.83 (d, J = 17.6 Hz, 1H, CH), 2.31–2.20 (m, 1H, CH), 1.99 (s, 3H, CH3), 1.57–1.44 (m, 4H, 2CH2), 1.29 (t, J = 7.1 Hz, 3H, CH3), 0.89 (dd, J = 17.0, 7.5 Hz, 6H, 2CH3). ESI-MS: m/z 567.10 [M + H]+, C32H42N2O7 (566.70).
Methyl 4-((4-((((1S,5R,6R)-6-acetamido-3-(ethoxycarbonyl)-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)methyl)phenoxy)methyl)benzoate (6b). White powder, 67% yield, mp: 141.5–143.5 °C. 1H NMR (400 MHz, CD3OD) δ: 8.01 (d, J = 8.2 Hz, 2H, 2Ph-H), 7.54 (d, J = 8.2 Hz, 2H, 2Ph-H), 7.24 (d, J = 8.5 Hz, 2H, 2Ph-H), 6.96 (d, J = 8.6 Hz, 2H, 2Ph-H), 6.77 (s, 1H, CH), 5.15 (s, 2H, CH2), 4.21 (q, J = 7.1 Hz, 2H, CH2), 4.06 (d, J = 7.9 Hz, 1H, CH), 3.95–3.87 (m, 4H, CH, CH3), 3.81 (d, J = 12.7 Hz, 1H, CH), 3.65 (d, J = 12.7 Hz, 1H, CH), 3.41–3.34 (m, 1H, CH), 2.90 (td, J = 10.0, 5.4 Hz, 1H, CH), 2.81 (dd, J = 17.6, 5.1 Hz, 1H, CH), 2.24 (ddt, J = 15.1, 9.4, 2.6 Hz, 1H, CH), 1.99 (s, 3H, CH3), 1.55–1.45 (m, 4H, 2CH2), 1.29 (t, J = 7.1 Hz, 3H, CH3), 0.89 (dt, J = 9.8, 7.4 Hz, 6H, 2CH3). ESI-MS: m/z 567.5 [M + H]+, C32H42N2O7 (566.70).
Methyl 3-((4-((((1S,5R,6R)-6-acetamido-3-(ethoxycarbonyl)-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)methyl)phenoxy)methyl)-4-methoxybenzoate (7b). Colorless sticky oil, 70% yield. 1H NMR (400 MHz, CD3OD) δ: 8.06 (d, J = 1.2 Hz, 1H, Ph-H), 8.00 (dd, J = 8.7, 1.8 Hz, 1H, Ph-H), 7.29 (d, J = 8.5 Hz, 2H, 2Ph-H), 7.10 (d, J = 8.7 Hz, 1H, Ph-H), 6.99 (d, J = 8.5 Hz, 2H, 2Ph-H), 6.80 (s, 1H, CH), 5.11 (s, 2H, CH2), 4.22 (q, J = 7.1 Hz, 2H, CH2), 4.10 (d, J = 8.1 Hz, 1H, CH), 4.05–3.93 (m, 5H, CH2, CH3), 3.86 (s, 3H, CH3), 3.82 (d, J = 12.9 Hz, 1H, CH), 3.43–3.36 (m, 1H, CH), 3.09 (td, J = 10.1, 5.6 Hz, 1H, CH), 2.88 (dd, J = 17.0, 4.7 Hz, 1H, CH), 2.42–2.30 (m, 1H, CH), 2.01 (s, 3H, CH3), 1.56–1.45 (m, 4H, 2CH2), 1.30 (t, J = 7.1 Hz, 3H, CH3), 0.89 (dd, J = 16.5, 7.5 Hz, 6H, 2CH3). ESI-MS: m/z 598.05 [M + H]+, C33H44N2O8 (596.72).
Methyl 4-((4-((((1S,5R,6R)-6-acetamido-3-(ethoxycarbonyl)-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)methyl)phenoxy)methyl)-3-chlorobenzoate (8b). White powder, 73% yield, mp: 159.5–161.5 °C. 1H NMR (400 MHz, CD3OD) δ: 8.03 (d, J = 1.1 Hz, 1H, Ph-H), 7.95 (dd, J = 8.1, 1.1 Hz, 1H, Ph-H), 7.69 (d, J = 8.0 Hz, 1H, Ph-H), 7.26 (d, J = 8.5 Hz, 2H, 2Ph-H), 6.97 (d, J = 8.5 Hz, 2H, 2Ph-H), 6.77 (s, 1H, CH), 5.21 (s, 2H, CH2), 4.21 (q, J = 7.1 Hz, 2H, CH2), 4.05 (d, J = 8.3 Hz, 1H, CH), 3.96–3.86 (m, 4H, CH, CH3), 3.81 (d, J = 12.7 Hz, 1H, CH), 3.64 (d, J = 12.8 Hz, 1H, CH), 3.37 (dt, J = 11.1, 5.5 Hz, 1H, CH), 2.92–2.85 (m, 1H, CH), 2.80 (dd, J = 17.5, 5.2 Hz, 1H, CH), 2.27–2.17 (m, 1H, CH), 1.99 (s, 3H, CH3), 1.57–1.46 (m, 4H, 2CH2), 1.29 (t, J = 7.1 Hz, 3H, CH3), 0.89 (dt, J = 9.7, 7.5 Hz, 6H, 2CH3). ESI-MS: m/z 601.37 [M + H]+, C32H41ClN2O7 (601.14).
Methyl 4-((4-((((1S,5R,6R)-6-acetamido-3-(ethoxycarbonyl)-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)methyl)phenoxy)methyl)-3-methoxybenzoate (9b). Colorless sticky oil, 71% yield. 1H NMR (400 MHz, CD3OD) δ: 7.64–7.59 (m, 2H, 2Ph-H), 7.50 (d, J = 7.7 Hz, 1H, Ph-H), 7.34 (d, J = 8.6 Hz, 2H, 2Ph-H), 7.01 (d, J = 8.6 Hz, 2H, 2Ph-H), 6.83 (s, 1H, CH), 5.15 (s, 2H, CH2), 4.23 (q, J = 7.1 Hz, 2H, CH2), 4.12 (dd, J = 20.2, 7.1 Hz, 2H, CH2), 4.08–4.02 (m, 1H, CH), 3.97 (d, J = 13.0 Hz, 1H, CH), 3.93 (s, 3H, CH3), 3.90 (s, 3H, CH3), 3.45–3.38 (m, 1H, CH), 3.30–3.23 (m, 1H, CH), 2.94 (dd, J = 17.5, 5.5 Hz, 1H, CH), 2.53–2.40 (m, 1H, CH), 2.02 (s, 3H, CH3), 1.59–1.46 (m, 4H, 2CH2), 1.30 (t, J = 7.1 Hz, 3H, CH3), 0.90 (q, J = 7.6 Hz, 6H, 2CH3). ESI-MS: m/z 597.16 [M + H]+, C33H44N2O8 (596.72).
Methyl 4-((4-((((1S,5R,6R)-6-acetamido-3-(ethoxycarbonyl)-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)methyl)phenoxy)methyl)-2-methoxybenzoate (10b). White powder, 67% yield, mp: 133.2–135.3 °C. 1H NMR (400 MHz, CD3OD) δ: 7.75 (d, J = 7.9 Hz, 1H, Ph-H), 7.25 (d, J = 8.6 Hz, 2H, 2Ph-H), 7.18 (s, 1H, Ph-H), 7.06 (d, J = 7.9 Hz, 1H, Ph-H), 6.96 (d, J = 8.6 Hz, 2H, 2Ph-H), 6.77 (s, 1H, CH), 5.13 (s, 2H, CH2), 4.21 (q, J = 7.1 Hz, 2H, CH2), 4.06 (d, J = 8.6 Hz, 1H, CH), 4.01–3.86 (m, 5H, CH2, CH3), 3.86–3.77 (m, 4H, CH, CH3), 3.66 (d, J = 12.7 Hz, 1H, CH), 3.41–3.34 (m, 1H, CH), 2.92 (d, J = 5.5 Hz, 1H, CH), 2.82 (d, J = 17.6 Hz, 1H, CH), 2.31–2.19 (m, 1H, CH), 1.99 (s, 3H, CH3), 1.58–1.45 (m, 4H, 2CH2), 1.29 (t, J = 7.1 Hz, 3H, CH3), 0.89 (dd, J = 17.0, 7.5 Hz, 6H, 2CH3). ESI-MS: m/z 597.83 [M + H]+, C33H44N2O8 (596.72).
Ethyl (3R,4R,5S)-4-acetamido-5-((4-((2-nitrobenzyl)oxy)benzyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate (11b). White powder, 68% yield, mp: 101.8–103.5 °C. 1H NMR (400 MHz, CD3OD) δ: 8.12 (d, J = 8.2 Hz, 1H, Ph-H), 7.83 (d, J = 7.7 Hz, 1H, Ph-H), 7.71 (t, J = 7.6 Hz, 1H, Ph-H), 7.55 (t, J = 7.8 Hz, 1H, Ph-H), 7.25 (d, J = 8.5 Hz, 2H, 2Ph-H), 6.95 (d, J = 8.5 Hz, 2H, 2Ph-H), 6.77 (s, 1H, CH), 5.44 (s, 2H, CH2), 4.21 (q, J = 7.1 Hz, 2H, CH2), 4.05 (d, J = 8.2 Hz, 1H, CH), 3.90 (dd, J = 10.2, 8.7 Hz, 1H, CH), 3.80 (d, J = 12.7 Hz, 1H, CH), 3.64 (d, J = 12.8 Hz, 1H, CH), 3.41–3.33 (m, 1H, CH), 2.93–2.76 (m, 2H, 2CH), 2.28–2.17 (m, 1H, CH), 1.99 (s, 3H, CH3), 1.57–1.43 (m, 4H, 2CH2), 1.29 (t, J = 7.1 Hz, 3H, CH3), 0.89 (dt, J = 9.9, 7.4 Hz, 6H, 2CH3). ESI-MS: m/z 554.5 [M + H]+, C30H39N3O7 (553.66).
Ethyl (3R,4R,5S)-4-acetamido-5-((4-((3-nitrobenzyl)oxy)benzyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate (12b). White powder, 70% yield, mp: 144.2–146.1 °C. 1H NMR (400 MHz, CD3OD) δ: 8.31 (s, 1H, Ph-H), 8.18 (d, J = 8.2 Hz, 1H, Ph-H), 7.84 (d, J = 7.7 Hz, 1H, Ph-H), 7.62 (t, J = 7.9 Hz, 1H, Ph-H), 7.25 (d, J = 8.5 Hz, 2H, 2Ph-H), 6.98 (d, J = 8.5 Hz, 2H, 2Ph-H), 6.77 (s, 1H, CH), 5.21 (s, 2H, CH2), 4.21 (q, J = 7.1 Hz, 2H, CH2), 4.05 (d, J = 8.2 Hz, 1H, CH), 3.95–3.86 (m, 1H, CH), 3.80 (d, J = 12.7 Hz, 1H, CH), 3.64 (d, J = 12.7 Hz, 1H, CH), 3.41–3.33 (m, 1H, CH), 2.88 (td, J = 9.9, 5.4 Hz, 1H, CH), 2.80 (dd, J = 17.5, 5.2 Hz, 1H, CH), 2.22 (ddt, J = 15.0, 9.0, 2.4 Hz, 1H, CH), 1.99 (s, 3H, CH3), 1.56–1.44 (m, 4H, 2CH2), 1.29 (t, J = 7.1 Hz, 3H, CH3), 0.89 (dd, J = 17.2, 7.5 Hz, 6H, 2CH3). ESI-MS: m/z 554.5 [M + H]+, C30H39N3O7 (553.66).
Ethyl (3R,4R,5S)-4-acetamido-5-((4-((4-nitrobenzyl)oxy)benzyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate (13b). White powder, 71% yield, mp: 118.9–120.1 °C. 1H NMR (400 MHz, CD3OD) δ: 8.24 (d, J = 8.7 Hz, 2H, 2Ph-H), 7.68 (d, J = 8.6 Hz, 2H, 2Ph-H), 7.25 (d, J = 8.5 Hz, 2H, 2Ph-H), 6.97 (d, J = 8.6 Hz, 2H, 2Ph-H), 6.77 (s, 1H, CH), 5.22 (s, 2H, CH2), 4.21 (q, J = 7.1 Hz, 2H, CH2), 4.06 (d, J = 8.2 Hz, 1H, CH), 3.90 (dd, J = 10.3, 8.6 Hz, 1H, CH), 3.80 (d, J = 12.7 Hz, 1H, CH), 3.64 (d, J = 12.7 Hz, 1H, CH), 3.41–3.34 (m, 1H, CH), 2.89 (td, J = 9.9, 5.4 Hz, 1H, CH), 2.80 (dd, J = 17.5, 5.2 Hz, 1H, CH), 2.22 (ddt, J = 15.0, 9.4, 2.6 Hz, 1H, CH), 1.99 (s, 3H, CH3), 1.57–1.44 (m, 4H, 2CH2), 1.29 (t, J = 7.1 Hz, 3H, CH3), 0.89 (dt, J = 9.4, 7.5 Hz, 6H, 2CH3). ESI-MS: m/z 554.24 [M + H]+, C30H39N3O7 (553.66).
Ethyl (3R,4R,5S)-4-acetamido-5-((4-((3-carbamoylbenzyl)oxy)benzyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate (14b). Light yellow powder, 62% yield, mp: 119.5–121.3 °C. 1H NMR (400 MHz, CD3OD) δ: 7.89 (s, 1H, Ph-H), 7.75 (d, J = 7.8 Hz, 1H, Ph-H), 7.55 (d, J = 7.7 Hz, 1H, Ph-H), 7.40 (t, J = 7.7 Hz, 1H, Ph-H), 7.23 (d, J = 8.6 Hz, 2H, 2Ph-H), 6.95 (d, J = 8.6 Hz, 2H, 2Ph-H), 6.74 (s, 1H, CH), 5.08 (s, 2H, CH2), 4.16 (q, J = 7.1 Hz, 2H, CH2), 4.04 (t, J = 7.0 Hz, 1H, CH), 4.00–3.88 (m, 2H, 2CH), 3.79 (d, J = 12.9 Hz, 1H, CH), 3.33 (dt, J = 11.3, 5.6 Hz, 1H, CH), 3.08 (td, J = 9.9, 5.4 Hz, 1H, CH), 2.82 (dd, J = 17.6, 5.3 Hz, 1H, CH), 2.39–2.26 (m, 1H, CH), 1.94 (s, 3H, CH3), 1.51–1.38 (m, 4H, 2CH2), 1.23 (t, J = 7.1 Hz, 3H, CH3), 0.88–0.77 (m, 6H, 2CH3). ESI-MS: m/z 552.55 [M + H]+, C31H41N3O6 (551.68).
Ethyl (3R,4R,5S)-4-acetamido-5-((4-((4-carbamoylbenzyl)oxy)benzyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate (15b). White powder, 71% yield, mp: 214.5–216.5 °C. 1H NMR (400 MHz, CD3OD) δ: 7.87 (d, J = 8.2 Hz, 2H, 2Ph-H), 7.53 (d, J = 8.1 Hz, 2H, 2Ph-H), 7.24 (d, J = 8.5 Hz, 2H, 2Ph-H), 6.96 (d, J = 8.5 Hz, 2H, 2Ph-H), 6.77 (s, 1H, CH), 5.14 (s, 2H, CH2), 4.21 (q, J = 7.1 Hz, 2H, CH2), 4.05 (d, J = 8.1 Hz, 1H, CH), 3.90 (dd, J = 10.2, 8.7 Hz, 1H, CH), 3.80 (d, J = 12.7 Hz, 1H, CH), 3.64 (d, J = 12.7 Hz, 1H, CH), 3.37 (dt, J = 11.3, 5.5 Hz, 1H, CH), 2.93–2.85 (m, 1H, CH), 2.81 (dd, J = 17.6, 5.0 Hz, 1H, CH), 2.28–2.18 (m, 1H, CH), 1.99 (s, 3H, CH3), 1.59–1.43 (m, 4H, 2CH2), 1.29 (t, J = 7.1 Hz, 3H, CH3), 0.89 (dt, J = 9.7, 7.4 Hz, 6H, 2CH3). ESI-MS: m/z 552.17 [M + H]+, C31H41N3O6 (551.68).
Ethyl (3R,4R,5S)-4-acetamido-3-(pentan-3-yloxy)-5-((4-((3-sulfamoylbenzyl)oxy) benzyl)amino)cyclohex-1-ene-1-carboxylate (16b). White powder, 64% yield, mp: 127.5–129.7 °C. 1H NMR (400 MHz, CD3OD) δ: 7.93 (s, 1H, Ph-H), 7.79 (d, J = 7.8 Hz, 1H, Ph-H), 7.60 (d, J = 7.7 Hz, 1H, Ph-H), 7.49 (t, J = 7.7 Hz, 1H, Ph-H), 7.22 (d, J = 8.6 Hz, 2H, 2Ph-H), 6.94 (d, J = 8.7 Hz, 2H, 2Ph-H), 6.73 (s, 1H, CH), 5.11 (s, 2H, CH2), 4.16 (q, J = 7.1 Hz, 2H, CH2), 4.02 (d, J = 8.1 Hz, 1H, CH), 3.94–3.83 (m, 2H, 2CH), 3.69 (d, J = 12.8 Hz, 1H, CH), 3.33 (dt, J = 11.3, 5.6 Hz, 1H, CH), 3.00–2.91 (m, 1H, CH), 2.84–2.75 (m, 1H, CH), 2.31–2.20 (m, 1H, CH), 1.94 (s, 3H, CH3), 1.52–1.40 (m, 4H, 2CH2), 1.23 (t, J = 7.1 Hz, 3H, CH3), 0.83 (dt, J = 9.7, 7.4 Hz, 6H, 2CH3). ESI-MS: m/z 588.52 [M + H]+, C30H41N3O7S (587.73).
Ethyl (3R,4R,5S)-4-acetamido-3-(pentan-3-yloxy)-5-((4-((4-sulfamoylbenzyl)oxy) benzyl)amino)cyclohex-1-ene-1-carboxylate (17b). White powder, 69% yield, mp: 76.8–78.9 °C. 1H NMR (400 MHz, CD3OD) δ: 7.83 (d, J = 8.3 Hz, 2H, 2Ph-H), 7.54 (d, J = 8.3 Hz, 2H, 2Ph-H), 7.28 (d, J = 8.6 Hz, 2H, 2Ph-H), 6.97 (d, J = 8.6 Hz, 2H, 2Ph-H), 6.77 (s, 1H, CH), 5.14 (s, 2H, CH2), 4.17 (q, J = 7.1 Hz, 2H, CH2), 4.11–3.95 (m, 3H, 3CH), 3.91 (d, J = 13.0 Hz, 1H, CH), 3.39–3.32 (m, 1H, CH), 3.23–3.16 (m, 1H, CH), 2.87 (dd, J = 17.5, 5.4 Hz, 1H, CH), 2.41 (ddd, J = 15.1, 9.7, 2.3 Hz, 1H, CH), 1.95 (s, 3H, CH3), 1.53–1.38 (m, 4H, 2CH2), 1.24 (t, J = 7.1 Hz, 3H, CH3), 0.83 (q, J = 7.6 Hz, 6H, 2CH3). ESI-MS: m/z 588.49 [M + H]+, C30H41N3O7S (587.73).
Ethyl (3R,4R,5S)-4-acetamido-5-((4-((4-(fluorosulfonyl)benzyl)oxy)benzyl)amino) -3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate (18b). White powder, 72% yield, mp: 109.5–111.3 °C. 1H NMR (400 MHz, CD3OD) δ: 8.07 (d, J = 8.4 Hz, 2H, 2Ph-H), 7.81 (d, J = 8.3 Hz, 2H, 2Ph-H), 7.38 (d, J = 8.6 Hz, 2H, 2Ph-H), 7.08 (d, J = 8.6 Hz, 2H, 2Ph-H), 6.85 (s, 1H, CH), 5.30 (s, 2H, CH2), 4.28–4.15 (m, 4H, CH2, 2CH), 4.13–4.03 (m, 2H, 2CH), 3.46–3.35 (m, 2H, 2CH), 2.96 (dd, J = 17.8, 5.7 Hz, 1H, CH), 2.59–2.48 (m, 1H, CH), 2.02 (s, 3H, CH3), 1.53 (tq, J = 13.5, 6.8 Hz, 4H, 2CH2), 1.30 (t, J = 7.1 Hz, 3H, CH3), 0.90 (q, J = 7.4 Hz, 6H, 2CH3). ESI-MS: m/z 591.51 [M + H]+, C30H39FN2O7S (590.71).
4.1.3. General Procedure for the Preparation of Compounds 1c–18c
The intermediates 1b–18b (0.8 mmol) were dissolved in methanol (30 mL) and 1 mol/L aqueous sodium hydroxide (10 mL) was added. The mixed solution was stirred at room temperature for 3–4 h. After completion of the reaction, the methanol was removed under reduced pressure. The residue was taken up in water (30 mL), and the pH value was adjusted to 2–3 with 3 mol/L HCl aqueous solution while the solid was precipitated from the water solution. After that, the solution was filtered and washed with water and dried under vacuum to afford the target compounds 1c–18c.
(3R,4R,5S)-4-acetamido-5-((4-((2-boronobenzyl)oxy)benzyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylic acid (1c). White powder, 65% yield, mp: 146.3–150.5 °C (along with the decomposition). 1H NMR (400 MHz, CD3OD) δ: 7.51–7.24 (m, 6H, 6Ph-H), 7.14–7.05 (m, J = 9.0 Hz, 2H, 2Ph-H), 6.86 (s, 1H, CH), 5.14 (s, 2H, CH2), 4.34 (d, J = 12.6 Hz, 1H, CH), 4.27–4.14 (m, 3H, 3CH), 3.62–3.52 (m, 1H, CH), 3.49–3.41 (m, 1H, CH), 3.02 (d, J = 16.9 Hz, 1H, CH), 2.70–2.59 (m, 1H, CH), 2.05 (s, 3H, CH3), 1.60–1.46 (m, J = 19.5, 9.7 Hz, 4H, 2CH2), 0.91 (q, J = 7.1 Hz, 6H, 2CH3). 13C NMR (100 MHz, CD3OD) δ: 159.5, 139.8, 131.3, 131.2, 131.2, 131.1, 128.2, 126.9, 126.3, 123.12, 115.1, 82.3, 74.5, 69.9, 54.7, 51.5, 25.7, 25.2, 22.0, 21.7, 8.4, 8.12. ESI-MS: m/z 525.4 [M + H]+, C28H37BN2O7 (524.42).
(3R,4R,5S)-4-acetamido-5-((4-((3-boronobenzyl)oxy)benzyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylic acid (2c). White powder, 53% yield, mp: 209.8–214.3 °C (along with the decomposition). 1H NMR (400 MHz, CD3OD) δ: 7.73–7.34 (m, 5H, 5Ph-H), 7.08 (t, J = 8.6 Hz, 2H, 2Ph-H), 6.97–6.79 (m, 2H, Ph-H, CH), 5.11 (d, J = 28.6 Hz, 2H, CH2), 4.33 (d, J = 13.0 Hz, 1H, CH), 4.27–4.15 (m, J = 15.2, 4.9 Hz, 3H, 3CH), 3.55 (td, J = 9.6, 5.9 Hz, 1H, CH), 3.46 (dt, J = 11.2, 5.5 Hz, 1H, CH), 3.03 (dd, J = 17.3, 5.5 Hz, 1H, CH), 2.64 (ddd, J = 9.5, 8.5, 4.6 Hz, 1H, CH), 2.06 (s, 3H, CH3), 1.55 (tq, J = 14.0, 6.8 Hz, 4H, 2CH2), 0.92 (q, J = 7.4 Hz, 6H, 2CH3). 13C NMR (100 MHz, CD3OD) δ: 173.5, 167.9, 159.8, 138.5, 136.5, 131.1, 130.6, 129.2, 128.1, 127.4, 122.9, 118.1, 115.4, 114.4, 113.8, 82.3, 74.6, 69.5, 54.6, 51.5, 47.1, 26.1, 25.7, 25.2, 22.0, 8.4, 8.2. ESI-MS: m/z 523.4 [M − H]−, C28H37BN2O7 (524.42).
(3R,4R,5S)-4-acetamido-5-((4-((4-boronobenzyl)oxy)benzyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylic acid (3c). White powder, 63% yield, mp: 168.3–172.1 °C (along with the decomposition). 1H NMR (400 MHz, CD3OD) δ: 7.70–7.55 (m, 1H, Ph-H), 7.41 (dd, J = 8.5, 3.9 Hz, 3H, 3Ph-H), 7.26 (d, J = 8.4 Hz, 1H, Ph-H), 7.08 (t, J = 8.3 Hz, 2H, 2Ph-H), 6.87 (d, J = 8.0 Hz, 1H, CH), 6.79 (d, J = 8.5 Hz, 1H, Ph-H), 5.16 (s, 1H, CH), 5.01 (s, 1H, CH), 4.33 (d, J = 13.0 Hz, 1H, CH), 4.26–4.15 (m, 3H, 3CH), 3.60–3.50 (m, J = 4.2 Hz, 1H, CH), 3.50–3.42 (m, 1H, CH), 3.08–2.97 (m, J = 8.5, 7.0 Hz, 1H, CH), 2.71–2.59 (m, 1H, CH), 2.06 (s, 3H, CH3), 1.55 (dq, J = 14.0, 7.0 Hz, 4H, 2CH2), 0.92 (q, J = 7.4 Hz, 6H, 2CH3). 13C NMR (100 MHz, CD3OD) δ: 159.9, 159.8, 157.1, 137.8, 133.7, 131.1, 131.1, 129.1, 127.5, 126.2, 124.7, 122.8, 122.6, 115.4, 115.3, 114.8, 82.3, 74.6, 69.7, 69.5, 54.6, 51.5, 29.5, 25.7, 25.2, 22.0, 8.4, 8.2. ESI-MS: m/z 523.4 [M − H]−, C28H37BN2O7 (524.42).
2-((4-((((1S,5R,6R)-6-acetamido-3-carboxy-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)methyl)phenoxy)methyl)benzoic acid (4c). White powder, 63% yield, mp: 177.1–178.9 °C. 1H NMR (400 MHz, CD3OD) δ: 8.06–7.97 (m, 1H, Ph-H), 7.66 (d, J = 7.7 Hz, 1H, Ph-H), 7.57–7.50 (m, 1H, Ph-H), 7.48–7.36 (m, 3H, 3Ph-H), 7.05 (d, J = 8.7 Hz, 2H, 2Ph-H), 6.85 (s, 1H, CH), 5.50 (s, 2H, CH2), 4.31 (d, J = 13.0 Hz, 1H, CH), 4.28–4.13 (m, 3H, 3CH), 3.60 (td, J = 10.3, 5.6 Hz, 1H, CH), 3.49–3.40 (m, 1H, CH), 3.02 (dd, J = 17.3, 5.4 Hz, 1H, CH), 2.71–2.58 (m, 1H, CH), 2.05 (s, 3H, CH3), 1.61–1.45 (m, 4H, 2CH2), 0.97–0.85 (m, 6H, 2CH3). 13C NMR (100 MHz, CD3OD) δ: 173.5, 169.2, 167.5, 159.8, 138.6, 137.0, 131.9, 131.2, 130.6, 129.2, 127.7, 127.2, 127.2, 122.9, 115.2, 82.3, 74.6, 68.0, 54.6, 51.5, 47.0, 26.0, 25.7, 25.2, 22.0, 8.4, 8.2. HRMS calcd. For C29H36N2O7 [M + H]+: 525.2595. Found: m/z 525.2595.
3-((4-((((1S,5R,6R)-6-acetamido-3-carboxy-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)methyl)phenoxy)methyl)benzoic acid (5c). White powder, 70% yield, mp: 146.2–148.5 °C. 1H NMR (400 MHz, CD3OD) δ: 8.08 (s, 1H, Ph-H), 7.96 (d, J = 7.8 Hz, 1H, Ph-H), 7.66 (d, J = 7.7 Hz, 1H, Ph-H), 7.52–7.38 (m, 3H, 3Ph-H), 7.08 (d, J = 8.6 Hz, 2H, 2Ph-H), 6.84 (s, 1H, CH), 5.19 (s, 2H, CH2), 4.32 (d, J = 13.0 Hz, 1H, CH), 4.28–4.09 (m, 3H, 3CH), 3.58 (td, J = 10.1, 5.6 Hz, 1H, CH), 3.47–3.40 (m, 1H, CH), 3.01 (dd, J = 17.3, 5.4 Hz, 1H, CH), 2.72–2.56 (m, 1H, CH), 2.04 (s, 3H, CH3), 1.62–1.46 (m, 4H, 2CH2), 0.90 (q, J = 7.6 Hz, 6H, 2CH3). 13C NMR (100 MHz, CD3OD) δ: 173.5, 168.3, 167.7, 159.6, 137.5, 136.7, 131.5, 131.3, 128.9, 128.3, 127.9, 123.1, 115.4, 82.3, 74.6, 69.0, 54.6, 51.5, 47.1, 26.0, 25.9, 25.2, 22.0, 8.4, 8.2. HRMS calcd for C29H36N2O7 [M + H]+: 525.2596. Found: m/z 525.2595.
4-((4-((((1S,5R,6R)-6-acetamido-3-carboxy-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)methyl)phenoxy)methyl)benzoic acid (6c). White powder, 71% yield, mp: 193.3–195.5 °C (along with the decomposition). 1H NMR (400 MHz, CD3OD) δ: 8.01 (d, J = 8.3 Hz, 2H, 2Ph-H), 7.53 (d, J = 8.2 Hz, 2H, 2Ph-H), 7.42 (d, J = 8.6 Hz, 2H, 2Ph-H), 7.07 (d, J = 8.7 Hz, 2H, 2Ph-H), 6.84 (s, 1H, CH), 5.20 (s, 2H, CH2), 4.32 (d, J = 13.0 Hz, 1H, CH), 4.27–4.13 (m, J = 18.8, 8.6 Hz, 3H, 3CH), 3.63–3.54 (m, J = 10.1, 5.6 Hz, 1H, CH), 3.48–3.40 (m, 1H, CH), 3.01 (dd, J = 17.3, 5.4 Hz, 1H, CH), 2.71–2.58 (m, 1H, CH), 2.04 (s, 3H, CH3), 1.60–1.45 (m, 4H, 2CH2), 0.90 (q, J = 7.6 Hz, 6H, 2CH3). 13C NMR (100 MHz, CD3OD) δ; 173.5, 168.3, 167.6, 159.5, 142.2, 136.7, 131.2, 130.3, 129.6, 127.8, 126.8, 123.1, 115.3, 82.3, 74.6, 68.9, 54.6, 51.5, 47.1, 26.0, 25.7, 25.2, 22.0, 8.4, 8.2. HRMS calcd for C29H36N2O7 [M + H]+: 525.2596. Found: m/z 525.2595.
3-((4-((((1S,5R,6R)-6-acetamido-3-carboxy-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)methyl)phenoxy)methyl)-4-methoxybenzoic acid (7c). White powder, 68% yield, mp: 152.1–154.1 °C. 1H NMR (400 MHz, CD3OD) δ: 8.06–7.95 (m, 2H, 2Ph-H), 7.40 (d, J = 8.6 Hz, 2H, 2Ph-H), 7.14–7.02 (m, 3H, 3Ph-H), 6.81 (s, 1H, CH), 5.14 (s, 2H, CH2), 4.31 (d, J = 13.0 Hz, 1H, CH), 4.24–4.13 (m, J = 10.5, 6.4 Hz, 3H, 3CH), 3.94 (s, 3H, CH3), 3.57–3.48 (m, 1H, CH), 3.47–3.40 (m, 1H, CH), 3.03 (d, J = 5.4 Hz, 1H, CH), 2.71–2.56 (m, J = 17.5, 9.9 Hz, 1H, CH), 2.04 (s, 3H, CH3), 1.60–1.47 (m, 4H, 2CH2), 0.90 (q, J = 7.4 Hz, 6H, 2CH3). 13C NMR (100 MHz, CD3OD) δ: 173.4, 168.4, 168.3, 160.7, 159.7, 135.9, 131.3, 131.2, 129.7, 128.6, 125.0, 123.0, 115.2, 109.8, 82.2, 74.6, 64.4, 55.0, 54.6, 51.56, 26.2, 25.7, 25.2, 22.0, 8.4, 8.2. HRMS calcd for C30H38N2O8 [M + H]+: 555.2703. Found: m/z 555.2701.
4-((4-((((1S,5R,6R)-6-acetamido-3-carboxy-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)methyl)phenoxy)methyl)-3-chlorobenzoic acid (8c). White powder, 66% yield, mp: 189.3–192.1 °C (along with the decomposition). 1H NMR (400 MHz, CD3OD) δ: 8.01–7.96 (m, J = 3.5 Hz, 1H, Ph-H), 7.89 (dd, J = 8.0, 1.3 Hz, 1H, Ph-H), 7.61 (d, J = 8.0 Hz, 1H, Ph-H), 7.43 (d, J = 8.6 Hz, 2H, 2Ph-H), 7.06 (d, J = 8.7 Hz, 2H, 2Ph-H), 6.80 (s, 1H, CH), 5.22 (s, 2H, CH2), 4.31 (d, J = 13.0 Hz, 1H, CH), 4.24–4.14 (m, 3H, 3CH), 3.56 (td, J = 9.9, 5.6 Hz, 1H, CH), 3.47–3.40 (m, 1H, CH), 3.00 (dd, J = 17.1, 5.7 Hz, 1H, CH), 2.69–2.58 (m, 1H, CH), 2.04 (s, 3H, CH3), 1.59–1.46 (m, 4H, 2CH2), 0.90 (q, J = 7.4 Hz, 6H, 2CH3). 13C NMR (100 MHz, CD3OD) δ: 173.4, 168.6, 168.2, 159.3, 138.3, 135.7, 134.2, 132.4, 131.2, 130.0, 129.0, 128.5, 127.8, 123.9, 115.2, 82.3, 74.8, 66.7, 54.7, 51.7, 47.1, 26.4, 25.8, 25.2, 22.0, 8.4, 8.2. HRMS calcd for C29H35ClN2O7 [M + H]+: 559.2210. Found: m/z 559.2206.
4-((4-((((1S,5R,6R)-6-acetamido-3-carboxy-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)methyl)phenoxy)methyl)-3-methoxybenzoic acid (9c). White powder, 68% yield, mp: 171.2–175.7 °C (along with the decomposition). 1H NMR (400 MHz, DMSO-d6) δ: 7.98–7.88 (m, 1H, Ph-H), 7.61–7.45 (m, 3H, 2Ph-H, NH), 7.29 (d, J = 8.4 Hz, 2H, 2Ph-H), 6.97 (d, J = 8.4 Hz, 2H, 2Ph-H), 6.61 (s, 1H, CH), 5.10 (s, 2H, CH2), 4.06 (d, J = 7.4 Hz, 1H, CH), 3.93–3.72 (m, 6H, CH3, 3CH), 3.39–3.32 (m, 1H, CH), 2.92 (dd, J = 12.0, 7.0 Hz, 1H, CH), 2.75–2.67 (m, 1H, CH), 2.22 (dd, J = 16.6, 10.2 Hz, 1H, CH), 1.87 (s, 3H, CH3), 1.50–1.32 (m, 4H, 2CH2), 0.87–0.75 (m, 6H, 2CH3). 13C NMR (100 MHz, DMSO-d6) δ: 170.5, 167.9, 167.7, 158.1, 157.0, 137.8, 132.5, 130.4, 130.2, 129.4, 128.8, 122.0, 115.0, 111.5, 81.4, 75.6, 64.8, 56.1, 54.6, 53.6, 48.3, 29.5, 26.1, 25.6, 23.6, 9.9, 9.4. HRMS calcd for C30H38N2O8 [M + H]+: 555.2706. Found: m/z 555.2701.
4-((4-((((1S,5R,6R)-6-acetamido-3-carboxy-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)methyl)phenoxy)methyl)-2-methoxybenzoic acid (10c). White powder, 72% yield, mp: 190.5–195.1 °C (along with the decomposition). 1H NMR (400 MHz, CD3OD) δ: 7.68 (d, J = 7.8 Hz, 1H, Ph-H), 7.39 (d, J = 8.5 Hz, 2H, 2Ph-H), 7.13 (s, 1H, Ph-H), 7.03 (d, J = 8.3 Hz, 3H, 3Ph-H), 6.75 (s, 1H, CH), 5.14 (s, 2H, CH2), 4.26 (d, J = 13.0 Hz, 1H, CH), 4.21–4.07 (m, J = 17.9, 10.8 Hz, 3H, 3CH), 3.85 (s, 3H, CH3), 3.51 (dd, J = 14.5, 9.1 Hz, 1H, CH), 3.46–3.38 (m, 1H, CH), 2.97 (dd, J = 17.3, 5.0 Hz, 1H, CH), 2.61 (dd, J = 17.2, 9.7 Hz, 1H, CH), 2.03 (s, 3H, CH3), 1.61–1.42 (m, 4H, 2CH2), 0.89 (dd, J = 13.5, 7.2 Hz, 6H, 2CH3). 13C NMR (100 MHz, CD3OD) δ: 173.3, 169.8, 169.4, 159.4, 158.5, 142.3, 134.9, 131.0, 130.9, 129.9, 123.8, 122.0, 118.6, 115.3, 110.4, 82.2, 74.9, 69.0, 55.0, 54.6, 51.8, 48.1, 26.7, 25.8, 25.2, 22.0, 8.4, 8.2. HRMS calcd for C30H38N2O8 [M + H]+: 555.2705. Found: m/z 555.2701.
(3R,4R,5S)-4-acetamido-5-((4-((2-nitrobenzyl)oxy)benzyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylic acid (11c). White powder, 68% yield, mp: 150.8–152.7 °C. 1H NMR (400 MHz, CD3OD) δ: 8.00 (d, J = 8.1 Hz, 1H, Ph-H), 7.70 (d, J = 7.7 Hz, 1H, Ph-H), 7.60 (t, J = 7.5 Hz, 1H, Ph-H), 7.45 (t, J = 7.5 Hz, 1H, Ph-H), 7.31 (d, J = 8.4 Hz, 2H, 2Ph-H), 6.95 (d, J = 8.4 Hz, 2H, 2Ph-H), 6.64 (s, 1H, CH), 5.36 (s, 2H, CH2), 4.17 (d, J = 12.9 Hz, 1H, CH), 4.11–3.98 (m, 3H, 3CH), 3.41–3.28 (m, 2H, 2CH), 2.86 (dd, J = 17.1, 4.3 Hz, 1H, CH), 2.49 (dd, J = 17.2, 9.2 Hz, 1H, CH), 1.92 (s, 3H, CH3), 1.48–1.37 (m, 4H, 2CH2), 0.79 (dd, J = 13.0, 7.3 Hz, 6H, 2CH3). 13C NMR (100 MHz, CD3OD) δ: 173.3, 169.5, 159.2, 147.8, 134.6, 133.4, 132.6, 131.1, 130.0, 128.9, 128.7, 124.5, 124.4, 115.2, 82.1, 74.7, 66.8, 54.7, 51.9, 48.1, 26.7, 25.8, 25.2, 21.9, 8.4, 8.2. HRMS calcd for C28H35N3O7 [M + H]+: 526.2551. Found: m/z 526.2548.
(3R,4R,5S)-4-acetamido-5-((4-((3-nitrobenzyl)oxy)benzyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylic acid (12c). White powder, 79% yield, mp: 152.5–155.1 °C. 1H NMR (400 MHz, CD3OD) δ: 8.33 (s, 1H, Ph-H), 8.20 (d, J = 8.2 Hz, 1H, Ph-H), 7.87 (d, J = 7.6 Hz, 1H, Ph-H), 7.65 (t, J = 7.9 Hz, 1H, Ph-H), 7.45 (d, J = 8.5 Hz, 2H, 2Ph-H), 7.12 (d, J = 8.5 Hz, 2H, 2Ph-H), 6.80 (s, 1H, CH), 5.28 (s, 2H, CH2), 4.31 (d, J = 13.0 Hz, 1H, CH), 4.17 (dd, J = 10.4, 7.2 Hz, 3H, 3CH), 3.53 (dd, J = 14.8, 9.4 Hz, 1H, CH), 3.49–3.42 (m, 1H, CH), 3.00 (dd, J = 16.2, 6.1 Hz, 1H, CH), 2.63 (dd, J = 17.4, 9.5 Hz, 1H, CH), 2.06 (s, 3H, CH3), 1.61–1.48 (m, 4H, 2CH2), 0.92 (dd, J = 13.2, 7.3 Hz, 6H, 2CH3). 13C NMR (100 MHz, CD3OD) δ: 173.4, 169.0, 159.2, 148.4, 139.5, 135.1, 133.1, 131.2, 129.5, 123.9, 122.4, 121.6, 115.3, 82.2, 74.7, 68.2, 54.7, 51.7, 47.1, 26.5, 25.7, 25.2, 22.0, 8.4, 8.2. HRMS calcd for C28H35N3O7 [M + H]+: 526.2550. Found: m/z 526.2548.
(3R,4R,5S)-4-acetamido-5-((4-((4-nitrobenzyl)oxy)benzyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylic acid (13c). khaki powder, 68% yield, mp: 184.1–187.5 °C (along with the decomposition). 1H NMR (400 MHz, CD3OD) δ: 8.26 (d, J = 8.7 Hz, 2H, 2Ph-H), 7.71 (d, J = 8.6 Hz, 2H, 2Ph-H), 7.46 (d, J = 8.6 Hz, 2H, 2Ph-H), 7.12 (d, J = 8.6 Hz, 2H, 2Ph-H), 6.87 (s, 1H, CH), 5.29 (s, 2H, CH2), 4.35 (d, J = 13.0 Hz, 1H, CH), 4.29–4.15 (m, 3H, 3CH), 3.62 (td, J = 10.0, 5.6 Hz, 1H, CH), 3.50–3.43 (m, 1H, CH), 3.03 (dd, J = 17.4, 5.3 Hz, 1H, CH), 2.72–2.60 (m, 1H, CH), 2.07 (s, 3H, CH3), 1.62–1.48 (m, 4H, 2CH2), 0.92 (q, J = 7.3 Hz, 6H, 2CH3). 13C NMR (100 MHz, CD3OD) δ: 173.5, 167.6, 159.3, 147.6, 144.6, 136.8, 131.3, 127.8, 127.7, 123.4, 123.3, 115.3, 82.3, 74.6, 68.3, 54.6, 51.5, 26.0, 25.7, 25.2, 22.0, 8.4, 8.2. HRMS calcd for C28H35N3O7 [M + H]+: 526.2549. Found: m/z 526.2548.
(3R,4R,5S)-4-acetamido-5-((4-((3-carbamoylbenzyl)oxy)benzyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylic acid (14c). White powder, 62% yield, mp: 138.2–140.5 °C. 1H NMR (400 MHz, CD3OD) δ: 7.98 (s, 1H, Ph-H), 7.84 (d, J = 7.7 Hz, 1H, Ph-H), 7.64 (d, J = 7.5 Hz, 1H, Ph-H), 7.57–7.38 (m, 3H, 3Ph-H), 7.11 (d, J = 8.5 Hz, 2H, 2Ph-H), 6.88 (s, 1H, CH), 5.20 (s, 2H, CH2), 4.35 (d, J = 13.0 Hz, 1H, CH), 4.22 (dt, J = 23.4, 9.4 Hz, 3H, 3CH), 3.60 (td, J = 10.0, 6.1 Hz, 1H, CH), 3.51–3.43 (m, 1H, CH), 3.04 (dd, J = 17.3, 4.7 Hz, 1H, CH), 2.66 (dd, J = 17.1, 9.6 Hz, 1H, CH), 2.07 (s, 3H, CH3), 1.63–1.47 (m, 4H, 2CH2), 1.00–0.84 (m, 6H, 2CH3). 13C NMR (100 MHz, CD3OD) δ: 173.5, 170.6, 159.6, 137.6, 136.9, 133.9, 131.2, 130.5, 128.4, 126.8, 126.4, 124.7, 123.0, 115.4, 82.3, 74.5, 69.2, 67.5, 54.7, 51.5, 29.5, 25.7, 25.2, 22.0, 8.4, 8.1. HRMS calcd for C29H37N3O6 [M + H]+: 524.2758. Found: m/z 524.2755.
(3R,4R,5S)-4-acetamido-5-((4-((4-carbamoylbenzyl)oxy)benzyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylic acid (15c). White powder, 73% yield, mp: 172.5–174.7 °C. 1H NMR (400 MHz, CD3OD) δ: 7.87 (d, J = 8.2 Hz, 2H, 2Ph-H), 7.52 (d, J = 8.2 Hz, 2H, 2Ph-H), 7.41 (d, J = 8.6 Hz, 2H, 2Ph-H), 7.07 (d, J = 8.6 Hz, 2H, 2Ph-H), 6.82 (s, 1H, CH), 5.19 (s, 2H, CH2), 4.31 (d, J = 13.0 Hz, 1H, CH), 4.26–4.13 (m, 3H, 3CH), 3.57 (td, J = 10.0, 5.7 Hz, 1H, CH), 3.44 (p, J = 5.6 Hz, 1H, CH), 3.00 (dd, J = 17.8, 4.9 Hz, 1H, CH), 2.63 (dd, J = 17.4, 9.8 Hz, 1H, CH), 2.04 (s, 3H, CH3), 1.59–1.46 (m, 4H, 2CH2), 0.90 (q, J = 7.3 Hz, 6H, 2CH3). 13C NMR (100 MHz, CD3OD) δ: 173.4, 170.5, 168.2, 159.5, 141.0, 136.2, 133.1, 131.2, 128.4, 127.5, 126.4, 123.3, 115.3, 82.3, 74.6, 68.9, 54.7, 51.6, 47.9, 26.2, 25.7, 25.2, 22.0, 8.4, 8.2. HRMS calcd for C29H37N3O6 [M + H]+: 524.2758. Found: m/z 524.2755.
(3R,4R,5S)-4-acetamido-3-(pentan-3-yloxy)-5-((4-((3-sulfamoylbenzyl)oxy) benzyl)amino)cyclohex-1-ene-1-carboxylic acid (16c). White powder, 70% yield, mp: 193.2–198.1 °C (along with the decomposition). 1H NMR (400 MHz, DMSO-d6) δ: 7.84 (d, J = 8.2 Hz, 2H, 2Ph-H), 7.61 (d, J = 8.3 Hz, 2H, 2Ph-H), 7.35–7.26 (m, 2H, 2Ph-H), 6.97 (d, J = 8.6 Hz, 2H, 2Ph-H), 6.61 (s, 1H, CH), 5.19 (s, 2H, CH2), 4.07 (d, J = 7.4 Hz, 1H, CH), 3.88–3.66 (m, J = 18.9, 13.8 Hz, 3H, 3CH), 3.40–3.32 (m, 1H, CH), 2.90 (d, J = 7.7 Hz, 1H, CH), 2.75–2.65 (m, J = 15.4, 4.7 Hz, 1H, CH), 2.27–2.12 (m, 1H, CH), 1.86 (s, 3H, CH3), 1.42 (qd, J = 14.0, 7.2 Hz, 4H, 2CH2), 0.87–0.74 (m, 6H, 2CH3). 13C NMR (100 MHz, DMSO-d6) δ: 170.3, 167.8, 157.7, 143.9, 143.8, 141.7, 137.9, 130.2, 129.3, 128.1, 126.3, 115.1, 81.4, 75.6, 68.8, 65.5, 54.5, 53.6, 30.9, 26.0, 25.6, 23.6, 9.9, 9.3. HRMS calcd for C28H37N3O7S [M + H]+: 560.2427. Found: m/z 560.2425.
(3R,4R,5S)-4-acetamido-3-(pentan-3-yloxy)-5-((4-((4-sulfamoylbenzyl)oxy) benzyl)amino)cyclohex-1-ene-1-carboxylic acid (17c). White powder, 69% yield, mp: 158.2–160.5 °C. 1H NMR (400 MHz, CD3OD) δ: 7.99 (s, 1H, Ph-H), 7.85 (d, J = 7.6 Hz, 1H, Ph-H), 7.66 (d, J = 7.5 Hz, 1H, Ph-H), 7.55 (t, J = 7.7 Hz, 1H, Ph-H), 7.42 (d, J = 8.4 Hz, 2H, 2Ph-H), 7.09 (d, J = 8.4 Hz, 2H, 2Ph-H), 6.83 (s, 1H, CH), 5.21 (s, 2H, CH2), 4.31 (d, J = 13.1 Hz, 1H, CH), 4.25–4.12 (m, 3H, 3CH), 3.53 (td, J = 9.7, 6.2 Hz, 1H, CH), 3.48–3.41 (m, 1H, CH), 3.00 (dd, J = 17.4, 5.1 Hz, 1H, CH), 2.62 (dd, J = 17.4, 9.6 Hz, 1H, CH), 2.04 (s, 3H, CH3), 1.60–1.46 (m, 4H, 2CH2), 0.90 (q, J = 7.1 Hz, 6H, 2CH3). 13C NMR (100 MHz, CD3OD) δ: 173.4, 168.0, 159.5, 144.1, 138.4, 136.1, 131.1, 130.6, 128.9, 128.3, 125.2, 124.5, 123.5, 115.4, 82.3, 74.5, 68.8, 54.6, 51.6, 47.9, 26.1, 25.7, 25.2, 21.9, 8.4, 8.1. HRMS calcd for C28H37N3O7S [M + H]+: 560.2428. Found: m/z 560.2425.
(3R,4R,5S)-4-acetamido-3-(pentan-3-yloxy)-5-((4-((4-sulfobenzyl)oxy)benzyl) amino)cyclohex-1-ene-1-carboxylic acid (18c). Off-white powder, 58% yield, mp: 244.5–248.7 °C (along with the decomposition). 1H NMR (400 MHz, DMSO-d6) δ: 12.55 (s, 1H, COOH), 8.77 (d, J = 165.8 Hz, 1H, NH), 8.01 (d, J = 9.1 Hz, 1H, NH), 7.60 (d, J = 8.1 Hz, 2H, 2Ph-H), 7.45–7.30 (m, 4H, 4Ph-H), 7.06 (d, J = 8.6 Hz, 2H, 2Ph-H), 6.64 (s, 1H, CH), 5.18 (s, 2H, CH2), 4.23–4.13 (m, 2H, overlapped, 2CH), 4.08 (d, J = 13.1 Hz, 1H, CH), 3.99 (dd, J = 20.0, 8.9 Hz, 1H, CH), 3.31–3.20 (m, 2H, 2CH), 2.83 (dd, J = 17.0, 4.9 Hz, 1H, CH), 2.58 (dd, J = 16.5, 11.0 Hz, 1H, CH), 1.91 (s, 3H, CH3), 1.51–1.34 (m, 4H, 2CH2), 0.81 (dt, J = 17.9, 7.3 Hz, 6H, 2CH3). 13C NMR (100 MHz, DMSO-d6) δ: 171.3, 167.3, 158.9, 148.2, 137.9, 137.6, 131.9, 127.98, 127.4, 126.1, 115.7, 81.7, 75.0, 69.2, 54.5, 51.2, 46.2, 26.2, 26.0, 25.5, 23.9, 9.8, 9.4. HRMS calcd for C28H36N2O8S [M + H]+: 561.2267. Found: m/z 561.2265