Paper
Organic & Biomolecular Chemistry
Ethyl 3-hydroxy-2-(2-oxo-1,2-dihydropyridin-1-yl)-3-phenyl- chloroacetate (5.98 mL, 50.5 mmol) was added and the
propanoate (55). In a 100 mL oven-dried flask with stir bar, mixture was stirred at 20 °C for 12 h. The reaction was
diisopropylamine (309 μL, 2.21 mmol) and anhydrous THF quenched with saturated NH4Cl (200 mL) and diluted with
(35.0 mL) were added via syringe under N2. The solution was EtOAc (750 mL). The organic layer was washed with water (6 ×
cooled to −78 °C in a dry ice/acetone bath before n-butyl 200 mL), dried over anhydrous Na2SO4, filtered, and concen-
lithium (1.38 mL of a 1.6 M solution in hexanes, 2.21 mmol) trated. The crude product was dissolved in DCM and purified
was added dropwise over 10 min. The solution was allowed to via flash chromatography (100 g SiO2, 0–85% EtOAc/hexanes)
stir for 30 min before a solution of 21 (400 mg, 2.21 mmol) in to afford pyridone 57 as a pale yellow oil (3.40 g, 42%). 1H
anhydrous THF (3.0 mL) was added dropwise over 5 min. The NMR (400 MHz, CDCl3) δ 7.30 (ddd, J = 9.2, 6.7, 2.1 Hz, 1H),
heterogenous solution was stirred at −78 °C for 1 h before 7.20 (ddd, J = 6.7, 2.1, 0.7 Hz, 1H), 6.49 (ddd, J = 9.2, 1.4, 0.7
benzaldehyde (0.247 mL, 2.43 mmol) was added, and the solu- Hz, 1H), 6.13 (td, J = 6.7, 1.4 Hz, 1H), 5.82 (ddt, J = 17.2, 10.5,
tion was stirred at −78 °C for 2 h. The reaction was quenched 5.7 Hz, 1H), 5.25 (dq, J = 17.2 1.5 Hz, 1H), 5.17 (dq, J = 10.5,
at −78 °C via the addition saturated aq. NH4Cl (15 mL) and 1.3 Hz, 1H), 4.60 (s, 2H), 4.58 (dt, J = 5.7, 1.4 Hz, 2H). 13C NMR
diluted with EtOAc (75 mL). The organic layer was separated, (100 MHz, CDCl3) δ 167.5, 162.4, 140.3, 138.0, 131.3, 121.0,
washed with brine, dried over anhydrous Na2SO4, filtered, and 119.0, 106.2, 66.3, 50.5. LC-MS tR = 2.30; m/z = 181.90 (M + H).
concentrated. The crude material was dissolved in DCM and
Prop-2-en-1-yl 3-hydroxy-2-(2-oxo-1,2-dihydropyridin-1-yl)-3-
purified via flash chromatography (50 g SiO2, 0–100% EtOAc/ phenylpropanoate (58). In an oven-dried 100 mL flask with stir
hexanes) to afford alcohol 55 as a colorless oil (307 mg, 48%). bar, anhydrous THF (50.0 mL) and diisopropylamine (1.55 mL,
1
The NMR spectra are complex due to diastereomers. H NMR 11.0 mmol) were added via syringe under N2. The solution was
(300 MHz, CDCl3) δ 7.59 (dd, J = 6.8, 1.3 Hz, 1H), 7.26–7.15 (m, cooled to −78 °C before n-butyl lithium (6.90 mL of a 1.6 M
12H), 6.80 (dd, J = 6.8, 1.5 Hz, 1H), 6.39 (d, J = 9.1 Hz, 1H), solution in hexanes, 11.0 mmol) was added dropwise over
6.28 (d, J = 9.1 Hz, 1H), 6.05 (td, J = 6.7, 1.2 Hz, 1H), 5.86 (td, J 5 min. The solution was stirred for 30 min before a solution of
= 6.7 Hz, 1.2 Hz, 1H), 5.81 (d, J = 4.3 Hz, 1H), 5.63 (d, J = 4.3 ester 57 (1.94 g, 10.0 mmol) in anhydrous THF (8.0 mL) was
Hz, 1H), 5.45 (d, J = 7.5 Hz, 1H), 4.74 (d, J = 7.5 Hz, 1H), added dropwise over 5 min and stirred at −78 °C for 1 h.
4.22–4.16 (m, 4H), 1.24–1.19 (m, 6H); 13C NMR (75 MHz, Benzaldehyde (1.53 mL, 15.1 mmol) was added and the result-
CDCl3) δ 169.4, 168.2, 162.9, 162.3, 140.2, 140.1, 139.5, 138.9, ing solution was stirred at −78 °C for 2 h. The reaction was
138.5, 137.9, 128.4, 128.3, 127.8, 126.4, 125.9, 120.3, 119.7, quenched at −78 °C with saturated aq. NH4Cl and diluted with
105.9, 105.6, 73.5, 72.1, 67.5, 63.5, 62.1, 62.1, 60.4, 21.1, 14.2, EtOAc (200 mL) and H2O (10 mL). The layers were
14.1, 14.0; LC-MS tR = 4.78, 4.92; m/z = 287.80 (M + H).
separated and the organic layer was washed with brine, dried
Ethyl 3-[(tert-butyldimethylsilyl)oxy]-2-(2-oxo-1,2-dihydropyr- over anhydrous Na2SO4, and concentrated. The crude yellow
idin-1-yl)-3-phenylpropanoate (56). The procedure for the syn- oil was dissolved in DCM and purified via flash chromato-
thesis of 37a was used with the following modifications: 55 graphy (100 g SiO2, 0–70% EtOAc/hexanes) to afford alcohol 58
1
(153 mg, 0.533 mmol), DCM (6.0 mL), 2,6-lutidine (74.4 μL, as a yellow oil (2.45 g, 82%). H NMR (400 MHz, CDCl3) δ 7.43
0.639 mmol) and TBSOTf (147 μL, 0.639 mmol) were used. The (d, J = 7.9 Hz, 1H), 7.27–7.22 (m, 13H), 6.71 (dd, J = 6.8, 1.5 Hz,
crude oil was dissolved in DCM and purified via flash chrom- 1H), 6.46 (d, J = 9.1 Hz, 1H), 6.40 (d, J = 8.8 Hz, 1H), 6.09 (td, J
atography (25 g SiO2, 0–50% EtOAc/hexanes) to yield 56 as a = 6.8, 1.3 Hz, 1H), 5.94–5.81 (m, 3H), 5.73 (s, 2H), 5.57 (d, J =
pale yellow oil (187 mg, 87%). 1H NMR (300 MHz, CDCl3) δ 7.9 Hz, 1H), 5.34–5.20 (m, 4H), 4.72–4.64 (m, 6H); 13C NMR
8.20 (dd, J = 6.9, 1.4 Hz, 1H), 7.87 (dd, J = 6.9, 1.4 Hz, 1H), (100 MHz, CDCl3) δ 169.2, 167.9, 163.1, 162.4, 140.3, 140.2,
7.56–7.38 (m, 11H), 6.62 (d, J = 9.2 Hz, 1H), 6.53 (d, J = 9.2 Hz, 139.4, 138.7, 138.5, 137.9, 131.4, 131.3, 128.5, 128.4, 128.4,
1H), 6.44–6.39 (m, 1H), 6.33–6.28 (m, 1H), 6.12 (d, J = 7.2 Hz, 128.0, 126.4, 125.9, 120.5, 120.0, 119.1, 119.0, 106.0, 105.8,
1H), 5.87 (d, J = 3.9 Hz, 1H), 5.44 (d, J = 7.2 Hz, 1H), 4.59–4.51 73.7, 72.1, 68.0, 66.6, 66.6, 64.0; LC-MS tR = 4.40, 4.53; m/z =
(m, 1H), 4.45–4.33 (m, 3H), 1.53 (t, J = 7.1 Hz, 3H), 1.46 (t, J = 299.75 (M + H).
7.1 Hz, 3H), 1.13 (s, 9H), 1.11 (s, 9H), 0.29 (s, 3H), 0.25 (s, 3H),
3-Hydroxy-2-(2-oxo-1,2-dihydropyridin-1-yl)-3-phenylpropanoic
0.02 (s, 3H), 0.00 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 169.0, acid (59). Alcohol 58 (1.90 g, 0.264 mmol) and Pd(PPh3)4
168.5, 162.2, 161.8, 139.6, 139.5, 139.4, 139.3, 138.7, 136.6, (12.2 mg, 0.0106 mmol) were added to a 500 mL oven-dried
128.3, 128.2, 128.2, 128.2, 127.0, 126.4, 120.4, 119.7, 105.4, flash with stir bar and sealed under N2. Anhydrous THF
104.5, 75.6, 75.4, 62.1, 61.9, 61.7, 61.5, 25.8, 25.8, 18.1, 18.1, (6.0 mL) and morpholine (24.2 μL, 0.277 mmol) were added
14.2, 14.1, −4.4, −4.6, −5.3, −5.5; LC-MS tR = 6.95; m/z = 401.95 via syringe and the reaction was stirred at 20 °C for 30 min.
(M + H).
After 30 min, analysis via LC-MS indicated consumption of
Prop-2-en-1-yl 2-(2-oxo-1,2-dihydropyridin-1-yl)acetate (57). starting material. The reaction mixture was concentrated, dry
NaH (60% dispersion in mineral oil, 1.77 g, 46.3 mmol) was loaded using celite, and purified using flash chromatography
added to a 500 mL oven-dried flask with stir bar and sealed (30 g C18, 0–95% MeOH/H2O w/0.1% formic acid) to afford
under N2. Anhydrous DMF (125 mL) was added and the sus- carboxylic acid 59 as a yellow oil (1.20 g, 73%). 1H NMR
pension was cooled to 0 °C in an ice bath. A solution of (400 MHz, CD3OD) δ 8.10 (d, J = 6.5 Hz, 1H), 7.44 (d, J = 6.5
2-hydroxypyridine (4.00 g, 42.1 mmol) in anhydrous DMF Hz, 1H), 7.36–7.15 (m, 10H), 6.37 (d, J = 9.0 Hz, 1H), 6.30–6.27
(25.0 mL) was slowly added and stirred for 1 h at 0 °C. Allyl (m, 1H), 6.14–6.10 (m, 1H), 5.73 (d, J = 3.8 Hz, 1H), 5.45 (d, J =
Org. Biomol. Chem.
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