Chemistry
Reactions employed oven- or flame-dried glassware under nitrogen unless otherwise noted. Thin layer chromatography (TLC) employed glass 0.25 mm silica gel plates with UV indicator. Flash chromatography columns were packed with 230–400 mesh silica gel as a slurry in the initial elution solvent. Gradient flash chromatography was conducted by adsorption of product mixtures on silica gel, packing over a short pad of clean silica gel as a slurry in hexane, and eluting with a continuous gradient as indicated. Nuclear magnetic resonance (NMR) data were obtained at operating frequencies indicated in the text and are reported in units of ppm. Infrared spectra were recorded using a single beam FT-IR spectrophotometer by standard transmission method. Low and high resolution mass spectra (TOF) were obtained from local instrumentation facilities services.
(S)-Ethyl 2-(2- (3-amiophenyl)thiazole-4-carboxamido)-3-phenylpropanoate (2)
Step 1: To a solution of compound 1 (5.56 g, 20 mmol) in 60 mL THF:H2O (1:1), was added NaOH aqueous solution (2.40 g, 60 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for 10 h till TLC showed that starting material all consumed. The solvent was removed by vaccum, the residue was adjusted the pH to 2 by 10% HCl. The white precipitate was isolated and washed with water, dried and used in next step with further purification. Step 2: The solid obtained in last step was dissolved in 100 mL DCM, SOCl2 (4.5 mL, 60 mmol) and 0.5 mL DMF was added at room temperature. The reaction mixture was allowed to stir at reflux condition for 4 h. The excess SOCl2 and DCM were removed under reduced pressure. The residue was diluted with 50 mL DCM and added through an additional funnel to a solution of l-Phe-OEt (3.86 g, 20 mmol) , Et3N (6.06 g, 60 mmol) in 100 mL DCM at 0 degree. The reaction mixture was allowed to stir at 0 degree for 30 min, then room temperature for 1 h. Water was added the reaction mixture, the aqueous layer was extracted with DCM (100 mL × 3). The organic layers were combined and dried over Na2SO4. The solvent was filtered, concentrated to afford pale yellow oil, which afforded a white solid after recrystallization from a co-solvent of EA/methanol. Yield: 87%.1H NMR (400 MHz, CDCl3) δ: 8.79 (t, J = 1.9, 1H), 8.34 (ddd, J = 8.2, 2.2, 0.9, 1H), 8.29–8.22 (m, 1H), 8.20 (s, 1H), 7.84 (d, J = 8.2, 1H), 7.69 (t, J = 8.0, 1H), 7.40–7.34 (m, 2H), 7.34–7.30 (m, 1H), 7.27–7.23 (m, 2H), 5.07 (dt, J = 8.2, 6.1, 1H), 4.23 (q, J = 7.1, 2H), 3.38–3.22 (m, 2H), 1.28 (t, J = 7.1, 3H). Step3. The above solid 7.40 g (17.4 mmol) was dissolved in MeOH,then about 0.5 g Pd/C (10%) was added. The reaction mixture was allowed to stir at 35 °C for 7 h under H2 (0.3 MPa) condition. After the reaction completed, the catalyst was removed by passing through a pad of celit, the filtrate was concentrated, and the residue (6.87 g brown solid) was used in next step directly.
(S)-Ethyl 2-(2-(3-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)phenyl)thiazole-4-carboxamido)-3-phenylpropanoate (3)
To a solution of Boc-l-Leu (4.02 g, 17.4 mmol) dissolved in 40 mL DCM,was added EDC (5.01 g, 26.1 mmol), HOBt (2.35 g, 17.4 mmol), and 1 mL DIPEA at room temperature. The reaction mixture was allowed to stir at room temperature for 1 h,then a solution of compound 4 (6.87 g, 17.4 mmol) in 20 mL DCM was added dropwisely. The reaction mixture stirred for 12 h at room temperature. Water 100 mL was added to the reaction mixture and the aqueous layer was extracted with DCM (100 mL × 3). The organic layers were combined, dried with Na2SO4, filtered and concentrated. The residue (pale yellow oil 10 g) was purified by chromatography (EA: PE = 1:4) to afford white solid 8.46 g, yield: 80%. 1H NMR (400 MHz, CDCl3) δ: 9.44 (s, 1H), 8.49 (d, J = 7.6, 1H), 7.92 (s, 1H), 7.84 (s, 1H), 7.74 (d, J = 7.8, 1H,), 7.36 (d, J = 7.3, 1H), 7.29 (s, 2H), 7.26 -7.21 (m, 1H), 7.18 (d, J = 7.6, 1H), 5.75 (s, 1H), 5.17 (dd, J = 15.0, 7.2, 1H), 4.53 (s, 1H), 4.23 (q, J = 7.1, 2H), 3.41–3.22 (m, 2H), 2.02 (d, J = 15.8, 1H), 1.82 (ddd, J = 25.6, 13.7, 7.0, 3H), 1.46–1.36 (m, 9H), 1.26 (t, J = 7.1, 4H), 1.03 (dd, J = 13.3, 6.3, 6H).
General synthesis method for compound Ia–Ie
Step 1: To a solution of D-N-Methyl-2-pipecolinic acid (0.04 g, 0.26 mmol) in 4 mL DCM,was added EDC (0.08 g, 0.39 mmol), HOBt (0.04 g, 0.26 mmol), 0.5 mL DIPEA at 0 °C. The reaction mixture was stirred for 1 h at room temperature. Meanwhile, a solution of compound 3 (0.16 g, 0.26 mmol) in 4 mL TFA was allowed to stir at room temperature for 3 h. The excess TFA was removed under reduced pressure, the residue was dissolved in 5 mL DCM and0.5 mL DIPEA. This solution was added to above reaction mixture under 20 °C. The reaction mixture was allowed to stir overnight at room temperature. Water 50 mL was added to reaction mixture, the aqueous layer was extracted with DCM (40 mL × 3). The organic layers were combined, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (EA:PE = 1:4) to afford white solid 0.13 g, yield: 81%.
Step 2: To a solution of above solid 0.11 g (0.17 mmol) in THF:H2O = 1:1 (10 mL, v:v), was added LiOH (0.02 g, 0.83 mmol). The reaction mixture was allowed to stir at room temperature till TLC showed that all starting material consumed. Solvent was removed under reduced pressure, the residue was diluted with water 50 mL, and adjusted with 10% HCl to pH = 2, extracted with DCM (40 mL × 3). The organic layers were combined, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (Chloroform: MeOH = 7: 1) to afford white solid 80 mg, yield: 77%. 1H NMR (CD3OD, 400 MHz) δ: 8.19 (s, 1H), 8.07 (s, 1H), 7.61 (dd, J = 16.0, 8.0, 2H), 7.35 (t, J = 7.9, 1H), 7.16 (dd, J = 17.6, 7.2, 4H), 7.08 (t, J = 6.8, 1H), 4.66–4.59 (m, 1H), 4.45 (dd, J = 9.8, 4.6, 1H), 3.30–3.25 (m, 1H), 2.97 (m, 1H), 2.69 (s, 3H), 1.83 (m, 3H), 1.66 (m, 6H), 1.51 (d, J = 12.5, 2H), 1.33–1.14 (m, 1H), 0.91 (dd, J = 10.8, 6.1, 6H); HRMS calcd for C32H39N5O5S [M+H]+ 606.2750, found 606.2755.
Ib: white solid, yield: 80%.1H NMR (CD3OD, 400 MHz) δ: 8.29 (s, 1H), 8.16 (d, J = 2.5, 1H), 7.71 (d, J = 6.6, 1H), 7.64 (t, J = 7.3, 1H), 7.44 (t, J = 7.9, 1H), 7.31–7.22 (m, 4H), 7.19 (d, J = 6.5, 1H), 4.63 (m, 1H), 4.45 (dd, J = 9.8, 4.6, 1H), 3.30–3.25 (m, 1H), 2.97 (m, 1H), 2.69 (s, 3H), 1.83 (m, 3H), 1.66 (m, 6H), 1.51 (d, J = 12.5, 2H), 1.33–1.14 (m, 1H), 0.91 (dd, J = 10.8, 6.1, 6H); 13C NMR (CD3OD, 100 MHz) δ: 20.3, 22.0, 24.7, 29.6, 37.9, 40.5, 42.8, 52.6, 54.3, 55.2, 55.9, 68.4, 115.3, 117.5, 118.2, 121.8, 123.2, 126.1, 127.8, 129.3, 133.2, 137.7, 139.1, 150.2, 161.0, 161.4, 161.7, 167.9, 171.9; HRMS calcd for C32H39N5O5S [M+H]+ 606.2750, found 606.2755.
Ic: white solid, yield: 79%.1H NMR (CD3OD, 400 MHz) δ: 8.23 (d, J = 1.7, 1H), 8.09 (s, 1H), 7.65 (d, J = 7.7, 1H), 7.59 (dd, J = 8.2, 1.1, 1H), 7.36 (t, J = 8.0, 1H), 7.18 (d, J = 4.4, 4H), 7.11 (m, 1H), 4.58–4.45 (m, 1H), 3.93 (q, J = 15.6, 1H), 3.34–3.23 (m, 1H), 3.12 (m, 1H), 2.84 (s, 6H), 1.62 (m, 3H), 1.24–1.16 (m, 2H), 0.92 (t, J = 6.2, 6H);13C NMR (CD3OD, 100 MHz) δ: 20.4, 22.0, 24.6, 36.9, 40.6, 43.0, 52.9, 57.8, 117.5, 121.9, 122.1, 123.7, 126.4, 128.1, 129.1, 132.9, 136.6, 138.9, 149.7, 161.2, 164.5, 168.1, 171.8; HRMS calcd for C29H35N5O5S [M+H]+ 566.2437, found 566.2434.
Id: white solid, yield: 75%. 1H NMR (CD3OD, 400 MHz) δ: 8.25 (s, 1H), 8.06 (s, 1H), 7.84–7.86 (m, 2H), 7.58–7.62 (m, 1H), 7.42–7.47 (m, 1H), 7.31–7.35 (m, 4H), 7.16–7.18 (m, 2H), 6.97–7.08 (m, 1H), 6.95–6.97 (m, 2H), 4.74–4.78 (m, 2H), 3.11–3.2 (m, 1H), 1.69–1.74 (m, 3H), 0.94–0.96 (d, J = 6.2, 6H), 0.78–0.80 (m, 1H);13C NMR (CD3OD, 100 MHz) δ: 20.9, 22.2, 36.9, 41.3, 50.9, 53.1, 117.7, 120.7, 121.0, 121.9, 122.0, 123.7, 126.5, 128.1, 129.0, 129.4, 130.8, 133.1, 136.6, 139.0, 139.6, 149.6, 161.7, 166.4, 168.1, 172.2, 174.9; HRMS calcd for C32H32N4O5S [M+H]+ 585.2093, found 585.2104.
Ie: white solid, yield: 81%. 1H NMR (CD3OD, 400 MHz) δ: 8.36 (s, 1H), 8.17 (d, J = 3.3, 1H), 7.96 (dd, J = 7.8, 1.7, 1H), 7.70 (dd, J = 11.7, 4.6, 2H), 7.58–7.48 (m, 1H), 7.44 (t, J = 7.9, 1H), 7.32–7.25 (m, 4H), 7.18 (t, J = 7.1, 2H), 7.08 (t, J = 7.5, 1H), 4.89–4.81 (m, 2H), 4.01 (s, 3H), 3.38 (d, J = 5.1, 1H), 3.25 (dd, J = 13.8, 7.6, 1H), 1.91–1.75 (m, 2H), 1.24 (dd, J = 13.3, 6.1, 1H), 1.06 (d, J = 5.8, 6H);13C NMR (CD3OD, 100 MHz) δ: 20.9, 22.1, 24.9, 36.9, 41.4, 53.1, 55.3, 111.6, 117.6, 120.6, 121.0, 121.9, 122.1, 123.7, 126.5, 128.1, 129.0, 129.4, 130.8, 133.1, 133.2, 136.6, 139.1, 149.6, 157.8, 166.4, 168.0, 172.1; HRMS calcd for C33H34N4O6S [M+H]+ 615.2277, found 615.2281.
(S)-Methyl 2-(3-aminobenzamido)-3-phenylpropanoate (4)
Step 1: To a solution of 3 nitrobenzoic acid (16.71 g, 100 mmol) in 200 mL DCM, was added SOCl2 (14 mL, 200 mmol) and 0.5 mL DMF at room temperature. The reaction mixture was allowed to stir at reflux condition for 5 h. The excess solvent was removed under reduced pressure, the residue was diluted with DCM 50 mL, and added via an additional funnel to a solution of l-Phe-OMe (17.91 g, 100 mmol), Et3N (30.6 g, 300 mmol) in DCM 100 mL at 0 °C. The reaction mixture was allowed to stir at 0 °C for 0.5 h, and then room temperature for 1 h till TLC showed that the reaction completed. Water 200 mL was added to the reaction mixture, the aqueous was extracted with DCM (150 mL × 3). The organic layers were combined, dried, filtered, and concentrated. The residue was re-crystallized from a co-solvent of ethyl acetate and methanol (1:6) to afford a white solid 29.19 g (yield 89%) and used in next step directly. Step 2: To a solution of above compound (29.15 g, 88.9 mmol) in 200 mL methanol, was added 1 g Pd/C (10%). The reaction mixture was allowed to stir under H2 (0.3 MPa) condition at 35 °C for 7 h. The reaction mixture was filtered through a pad of Celite, the filtration was concentrated to afford a gray solid 27.77 g as crude product, which was purified via re-crystallization from methanol and ethyl acetate (1:5) 24.77 g (93%). 1H NMR (400 MHz, CDCl3) δ 7.30–7.33 (m, 4H), 7.17–7.22 (m, 4H), 7.13–7.15 (m,1H), 6.89 (m, 1H), 6.38 (m, 1H), 5.10–5.12 (m, 1H), 3.80 (s, 3H), 3.31 (dd, J = 14.0, 5.8 Hz, 1H), 3.24 (dd, J = 14.0, 5.9 Hz, 1H). 13C NMR (CDCl3, 100 MHz) δ: 37.9, 52.4, 53.5, 113.9, 116.7, 118.3, 127.2, 128.6, 129.3, 135.0, 135.5, 135.8, 146.5, 167.0, 172.0; HRMS calcd for C17H18N2O3 [M+H]+ 299.1317, found 299.1314.
(S)-Methyl 2-(5-amino-2-bromobenzamido)-3-phenylpropanoate (4a)
Made by the same method as described in compound 4. 1H NMR (400 MHz, CDCl3) δ 7.30–7.34 (m, 6H), 7.21–7.26 (m, 1H), 6.68 (s, 1H), 6.61–6.65 (m, 2H), 5.09–5.13 (m, 1H), 3.81 (s, 3H), 3.22–3.36 (m, 2H). 13C NMR (CDCl3, 100 MHz) δ: 37.8, 51.8, 53.7, 116.0, 117.9, 122.0, 127.2, 128.6, 129.4, 133.8, 134.2, 167.0, 146.6, 166.5, 171.2; HRMS calcd for C17H17BrN2O3 [M+H]+ 377.0423, found 377.0418.
(S)-Methyl 2-(3-((S)-2-(9 (tert-butoxycarbonyl)amino)-3-methylbutanamido)benzamido)-3-phenylpropanoate (5)
To a solution of Boc-l-Val (8.68 g, 40.0 mmol) in 60 mL DCM, was added EDC (9.98 g, 52.0 mmol), HOBt (5.40 g, 40.0 mmol), and 3 mL DIPEA at 0 °C. The reaction mixture was allowed to stir room temperature for 1 h. Then a solution of compound 6 (11.92 g, 40.0 mmol) in DCM was added to above reaction mixture. The resulting reaction mixture was stirred at room temperature for 1 h. Water 150 mL was added, and the aqueous layer was extracted with DCM (120 mL × 3). The organic layers were combined, dried, filtered, and concentrated. The residue was purified by a chromatography (EA: PE = 1:4) to afford white solid 16.70 g (yield: 84%). 1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 7.63–7.71 (m, 2H), 7.18–7.34 (m, 6H), 7.08 (m, 1H), 6.97 (m, 1H), 5.83–5.86 (m, 1H), 5.18–5.19 (m, 1H), 4.30–4.34 (m,1H), 3.78 (s, 3H), 3.26–3.28 (m, 2H), 2.17–2.18 (m, 1H), 1.56 (s, 9H), 1.04–1.14 (m, 6H). 13C NMR (100 MHz, CDCl3) δ: 19.2, 28.3, 31.0, 38.1, 52.3, 53.7, 60.9, 80.7, 117.3, 122.1, 123.0, 126.9, 128.5, 128.9, 129.3, 134.8, 136.5, 137.3, 167.3, 168.3, 171.4, 172.7; HRMS calcd. for C27H35N3O6[M+H]+ Exact Mass: 498.2526, found 498.2538.
(S)-Methyl2-(2-bromo-5-((S)-2-(tert-butoxycarbonyl)-3-methylbutanamido)benzamido)-3-phenylpropanoate (5a)
Made by the same method as described in compound 5. 1H NMR (CDCl3, 400 MHz) δ: 9.17 (br s, 1H), 7.74 (m, 1H), 7.49–7.51 (m, 1H), 7.30–7.32 (m, 5H), 7.12–7.14 (m, 1H), 6.81 (br s, 1H), 6.01 (m, 1H), 5.15–5.21 (m, 1H), 4.28 (m, 1H), 3.81 (s, 3H), 3.25–3.35 (m, 2H), 2.07–2.17 (m, 1H), 1.47 (s, 9H), 1.06–1.11 (m, 6H). 13C NMR (CDCl3, 100 MHz) δ: 19.1, 28.3, 29.7, 38.2, 52.3, 53.6, 60.7, 82.1, 113.9, 117.4, 118.9, 121.1, 127.0, 128.5, 129.4, 133.8, 136.1, 136.7, 157.3, 165.3, 166.6, 172.3. HRMS calcd for C27H34BrN3O6 [M+H]+ 576.1631, found 576.1628.
(S)-methyl 2-(3-((S)-2-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)-3-methylbutanamido)benzamido)-3-phenylpropanoate (6)
To a solution of Boc-l-Leu (4.50 g, 19.5 mmol) in 50 mL DCM, was added EDC (4.87 g, 25.4 mmol), HOBt (2.63 g, 19.5 mmol), and 1 mL DIPEA at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Meanwhile, a solution of compound 7 (9.69 g, 19.5 mmol) in 4 mL TFA was stirred for 3 h at room temperature. The access of TFA was removed under reduced pressure. The residue was diluted in 25 mL DCM, and added to above reaction mixture via an additional funnel. The resulting reaction mixture was allowed to stir at room temperature overnight. Water 100 mL was added, and the aqueous layer was extracted with DCM (100 mL × 3). The organic layers were combined, dried, filtered, and concentrated. The residue was purified by a chromatography (EA:PE = 1:3) to afford compound 6 as white solid 9.89 g (yield 83%). 1H NMR (400 MHz, CDCl3) δ: 9.42 (s, 1H), 8.00 (d, J = 7.7, 1H), 7.92 (s, 1H), 7.30 (dd, J = 14.6, 7.6, 4H), 7.25 (d, J = 7.2, 1H), 7.16 (d, J = 6.9, 2H), 6.91 (d, J = 7.2, 1H), 6.85 (d, J = 7.6, 1 H), 5.74 (s, 1H), 5.06 (dd, J = 13.4, 6.0, 1H), 4.67–4.37 (m, 1H), 4.15 (s, 1H), 3.73 (s, 3H), 3.25 (qd, J = 13.9, 5.9, 2H), 2.25 (d, J = 6.3, 1H), 1.74 (dd, J = 13.3, 6.6, 1H), 1.62 (dd, J = 9.4, 4.9, 2 H), 1.37 (s, 9H), 1.00 (d, J = 6.7, 6H), 0.91 (d, J = 6.5, 6H).
13C NMR (CDCl3, 100 MHz) δ:17.3, 22.2, 22.6, 28.3, 31.1, 37.1, 41.2, 51.9, 52.6, 53.6, 58.6, 79.9, 117.7, 122.1, 123.1, 126.9, 127.9, 128.9, 129.2, 134.9, 138.7, 139.6, 156.1, 167.7, 171.3, 171.6, 172.1. HRMS calcd for C33H46N4O7 [M+H]+ 611.3366, found 611.3358.
(S)-Methyl2-(2-bromo-5-((S)-2-((S)-2-(tert-butoxycarbonyl)-4-methylpentanamido)-3-methylbutanamido)benzamido)-3-phenylpropanoate (6a)
Made by the same method as described in compound 6. 1H NMR (CDCl3, 400 MHz) δ: 9.32 (br s, 1H), 7.89–7.99 (m, 1H), 7.82 (m, 1H), 7.26–7.31 (m, 4H), 7.15–7.17 (m, 2H), 6.84–6.86 (m, 2H), 5.75 (br s, 1H), 4.94–4.98 (m, 1H), 4.56–4.60 (m, 1H), 4.15 (m, 1H), 3.75 (s, 3H), 3.17–3.29 (m, 2H), 2.23–2.25 (m, 1H), 1.74–1.77 (m, 1H), 1.60–1.63 (m, 2H), 1.37 (s, 9H), 0.90–1.01 (d, J = 8.0, 12H). 13C NMR (CDCl3, 100 MHz) δ:17.3, 22.2, 22.5, 28.3, 31.0, 37.1, 41.2, 51.9, 52.7, 53.6, 58.9, 79.7, 118.9, 122.1, 123.0, 126.9, 128.6, 128.9, 129.3, 134.9, 137.7, 139.2, 156.5, 167.7, 171.2, 171.5, 172.3. HRMS calcd for C33H45BrN4O7 [M+H]+ 689.2472, found 689.2481.
Compounds IIa–IIg were synthesized by the same method as described in compound Ia.
IIa: white solid, yield 80%. 1H NMR (CD3OD, 400 MHz) δ: 7.98 (d, J = 8.8, 1H), 7.72 (dd, J = 8.0, 7.1, 1H), 7.45 (dd, J = 7.7, 1.3, 1H), 7.36 (td, J = 7.9, 1.6, 1H), 7.31–7.19 (m, 4 H), 7.15 (td, J = 7.1, 1.5, 1H), 4.78–4.63 (m, 1H), 4.53–4.40 (m, 1H), 4.36 (d, J = 7.6, 1H), 3.35–3.29 (m, 2H), 2.52 (d, J = 2.9, 1H), 2.45 (d, J = 2.7, 3H), 2.15 (dd, J = 13.9, 6.9, 1H), 1.94 (d, J = 8.1, 1H), 1.81 (d, J = 13.0, 1H), 1.68 (tdd, J = 15.2, 10.9, 4.5, 6H), 0.95 (ddd, J = 11.5, 8.5, 4.5, 12H); 13C NMR (CD3OD, 100 MHz) δ: 17.2, 18.4, 20.3, 20.9, 22.0, 24.6, 29.2, 30.5, 39.9, 42.5, 46.3, 52.0, 54.9, 59.2, 67.8, 118.7, 122.4, 122.6, 125.6, 125.9, 127.7, 128.6, 129.1, 135.3, 138.0, 170.0, 170.6, 171.9, 172.1, 173.2; HRMS calcd for C34H47N5O6 [M+H]+ 622.3605, found 622.3599.
IIb: white solid, yield 79%.1H NMR (CD3OD, 400 MHz) δ: 7.95 (d, J = 12.5, 1H), 7.68 (dd, J = 19.6, 8.2, 1H), 7.45 (d, J = 7.9, 1H), 7.37 (t, J = 7.9, 1H), 7.24 (q, J = 7.2, 3H), 7.15 (t, J = 6.6, 1H), 4.60–4.47 (m, 1H), 4.48–4.37 (m, 1H), 4.38–4.26 (m, 1H), 3.50 (d, J = 9.6, 1H), 3.13 (s, 1H), 2.94–2.72 (m, 1H), 2.15 (ddd, J = 40.8, 24.7, 14.9, 2H), 1.86 (dd, J = 26.9, 15.5, 2H), 1.69 (dt, J = 13.8, 9.6, 4H), 1.10–0.84 (m, 12H). 13C NMR (CD3OD, 100 MHz) δ: 17.2, 18.4, 20.2, 21.1, 22.0, 24.6, 29.3, 30.9, 40.1, 42.5, 45.9, 52.1, 55.0, 59.2, 67.8, 118.8, 122.4, 122.7, 125.6, 125.9, 127.7, 128.6, 129.3, 135.4, 138.0, 170.1, 170.3, 171.9, 174.4, 174.9. HRMS calcd for C34H47N5O6 [M+H]+ 622.3605, found 622.3599.
IIc: white solid, yield 80%.1H NMR (CD3OD, 400 MHz) δ: 8.63 (t, J = 1.9, 1H), 8.33–8.25 (m, 1 H), 8.15 (d, J = 7.8, 1H), 7.63 (d, J = 8.0, 1H), 7.61–7.54 (m, 1H), 7.34 (d, J = 7.8, 1H), 7.27 (t, J = 7.9, 1H), 7.22 –7.13 (m, 4H), 7.12–7.05 (m, 1H), 4.73 (dd, J = 9.5, 4.9, 3H), 4.65 (dd, J = 9.4, 4.3, 1H), 4.26 (t, J = 6.6, 1H), 3.30 (s, 1H), 3.13–2.93 (m, 1H), 2.07 (dd, J = 13.2, 6.7, 1H), 1.64 (ddd, J = 26.5, 10.3, 5.4, 3H), 0.99–0.81 (m, 12H); 13C NMR (CD3OD, 100 MHz) δ: 20.5, 22.0, 24.8, 30.9, 36.8, 40.1, 52.7, 54.3, 59.5, 118.9, 122.1, 122.7, 123.0, 125.8, 126.3, 128.1, 128.6, 128.8, 129.6, 133.2, 134.8, 135.5, 137.2, 138.1, 148.2, 166.5, 168.5, 170.9, 173.4, 173.6; HRMS calcd for C34H39N4O8 [M+H]+ 646.2877, found 646.2880.
IId: white solid, yield 78%. 1H NMR (CD3OD, 400 MHz) δ: 7.92–7.83 (m, 1H), 7.76 (d, J = 7.4, 2H), 7.57 (d, J = 5.3, 1H), 7.43 (s, 1H), 7.34 (dd, J = 14.3, 7.0, 3H), 7.23 (t, J = 7.8, 1H), 7.14 (dd, J = 14.2, 7.4, 4H), 7.03 (t, J = 7.0, 1H), 4.63 (d, J = 9.8, 2H), 4.27 (d, J = 7.4, 1H), 3.61 (dq, J = 13.2, 6.6, 4H), 3.00 (dd, J = 13.7, 8.3, 1H), 2.06 (dd, J = 13.6, 6.8, 1H), 1.76–1.52 (m, 3H), 0.95–0.81 (m, 12H). 13C NMR (CD3OD, 100 MHz) δ: 17.3, 17.9, 18.1, 18.4, 30.5, 37.8, 55.6, 58.9, 59.4, 117.1, 125.8, 127.0, 127.6, 128.1, 128.8, 129.3, 131.3, 134.1, 134.7, 135.7, 137.6, 143.6, 144.3, 161.0, 169.0, 170.5, 171.3, 172.8; HRMS calcd for C34H40N4O6 [M+H]+ 601.3026, found 601.3029.
IIe: white solid, yield 82%.1H NMR (CD3OD, 400 MHz) δ: 8.06 (d, J = 6.2, 1H), 8.03–7.95 (m, 1H), 7.85–7.77 (m, 1H), 7.66–7.59 (m, 1H), 7.56 (d, J = 7.8, 1H), 7.49 (t, J = 7.8, 1H), 7.44–7.34 (m, 4H), 7.34–7.24 (m, 2H), 7.17 (t, J = 7.5, 1H), 4.93 (dd, J = 9.3, 4.6, 1H), 4.86 (t, J = 7.1, 1H), 4.46 (d, J = 7.5, 1H), 4.10 (s, 3H), 3.47 (d, J = 4.8, 1H), 3.22 (dd, J = 13.8, 9.4, 1H), 2.34–2.24 (m, 1H), 1.89–1.77 (m, 3H), 1.13 (ddd, J = 18.5, 8.7, 4.4, 12H); 13C NMR (CD3OD, 100 MHz) δ: 19.3, 20.7, 22.0, 24.7, 30.8, 36.8, 40.8, 52.3, 55.1, 59.3, 111.5, 118.9, 120.5, 121.1, 122.7, 123.0, 126.3, 128.0, 128.6, 128.9, 130.6, 132.9, 134.9, 137.4, 138.2, 139.5, 157.6, 166.7, 170.7, 171.5, 173.5; HRMS calcd for C35H42N4O7 [M+H]+ 631.3132, found 631.3136.
IIf: white solid, yield 78%. 1H NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.39–7.41 (d, J = 8.6 Hz, 1H), 7.32–7.33 (m, 2H), 7.14–7.22 (m, 3H), 6.98–7.02 (m, 1H), 4.63–4.66 (dd, J = 9.5, 4.0 Hz, 1H), 4.22–4.34 (m, 2H), 3.20–3.21 (m, 4H), 2.80–2.83 (m, 1H), 2.47–2.72 (m, 1H), 2.56 (s, 3H), 2.15–2.17 (m, 1H), 1.39–1.76 (m, 8H), 0.71–0.97 (m, 12H); 13C NMR (CD3OD, 100 MHz) δ:17.2, 18.3, 20.2, 21.9, 23.7, 24.6, 29.2, 30.4, 39.9, 42.5, 51.9, 54.9, 59.2, 67.8, 117.6, 122.5, 122.6, 125.9, 127.7, 128.6, 129.1, 135.3, 138.0, 139.7, 170.0, 170.6, 171.9, 172.1, 173.2; HRMS calcd for C34H46BrN5O6 [M+H]+ 700.2631, found 700.2636.
IIg: white solid, yield 72%. 1H NMR (400 MHz, MeOD) δ 7.99 (s, 1H), 7.72–7.74 (d, J = 8.6 Hz, 1H), 7.44–7.46 (m, 2H), 7.36–7.38 (m, 2H), 7.15–7.17 (m, 2H), 4.69–4.71 (m, 1H), 4.44–4.47 (m, 1H), 4.35–4.37 (m, 1H),3.73–3.75 (m, 1H), 3.32–3.35 (m, 1H),3.20–3.24 (m, 1H), 2.45–2.52 (m, 1H), 2.44 (s, 3H), 2.16–2.18 (m, 1H), 1.62–1.80 (m, 8H), 1.36–1.37 (m, 2H), 0.91–1.20 (m, 12H); 13C NMR (CD3OD, 100 MHz) δ: 17.3, 18.4, 20.3, 20.9, 21.8, 23.7, 24.6, 29.3, 30.5, 39.9, 42.5, 51.9, 54.9, 59.3, 65.8, 117.8, 122.5, 122.6, 125.9, 127.7, 128.7, 129.1, 135.3, 138.0, 139.7, 170.0, 170.6, 171.9, 172.1, 173.0; HRMS calcd for C34H46BrN5O6 [M+H]+ 700.2631, found 700.2634.