D.-R. Hou et al. / Tetrahedron: Asymmetry 16 (2005) 3858–3864
3863
(m, 1H), 1.79–1.72 (m, 3H), 1.69–1.62 (m, 2H); 13C NMR
(125 MHz, D2O+CD3OD): d 170.0, 138.9, 131.1, 130.0,
127.9, 68.3, 44.0, 35.4, 32.4, 22.7, 20.5; HRMS (FAB)
[M+H]+ (C13H18NO2) calcd 220.1338, found 220.1338.
CDCl3): d 7.45–7.29 (m, 5H), 5.98–5.79 (m, 1H), 5.17–
5.13 (m, 2H), 4.39–4.35 (m, 2H), 4.26–4.07 (m, 1H),
2.83–2.55 (m, 3H), 2.46–2.40 (m, 1H), 2.12 (dt,
J = 3.9, 13.8 Hz, 1H), 1.81–1.68 (m, 1H), 1.59–1.52
(m, 2H), 1.50–1.40 (m, 2H); 13C NMR (125 MHz,
CDCl3): d 172.6, 137.8, 133.4, 128.9, 128.3, 128.1,
118.1, 72.9, 65.5, 56.8, 42.2, 38.0, 30.9, 25.2, 20.5;
HRMS (FAB) [M+H]+ (C17H22NO2) calcd 272.1651;
found 272.1648.
3.5. Diastereoselective alkylation to form chiral quater-
nary carbon
3.5.1. Preparation of (4R,9aS)-9a-propyl-4-phenylhexa-
hydropyrido[2,1-c][1,4]oxazin-1-one 8c. Potassium bis-
(trimethylsilyl)amide (0.5 M, 1.7 mL, 0.86 mmol) was
added to a solution of 4 (100 mg, 0.43 mmol) in THF
(3 mL) at ꢀ78 °C dropwise. After 30 min at ꢀ78 °C,
HMPA (150 lL, 0.86 mmol) and propyl iodide
(214 lL, 2.2 mmol) were added to the reaction sequen-
tially. The reaction was maintained at ꢀ70 to ꢀ78 °C
for 1.5 h, and then quenched with saturated ammonium
chloride (3 mL), diluted with water (5 mL), and
extracted with ethyl acetate. The organic layer was
washed with water and saturated sodium chloride, dried
over anhydrous sodium sulfate, filtered, concentrated,
and purified by column chromatography (SiO2: ethyl
acetate/hexanes) to provide compound 8c (88 mg,
3.5.5. (4R,9aR)-9a-Benzyl-4-phenylhexahydropyrido[2,1-
c][1,4]oxazin-1-one 8e. Rf 0.44 (ethyl acetate/hexanes
25
1
1:8); ½aꢁD ¼ ꢀ143:1 (c 1, CHCl3); H NMR (500 MHz,
CDCl3): d 7.35–7.25 (m, 7H), 7.25–7.20 (m, 3H), 4.27–
4.25 (m, 2H), 4.06 (dd, J = 6.3, 7.7 Hz, 1H), 3.40 (d,
J = 13.7 Hz, 1H), 3.27 (d, J = 13.7 Hz, 1H), 2.65 (dt,
J = 3.0, 11.8 Hz, 1H), 2.53–2.50 (m, 1H), 2.10–2.07
(m, 1H), 1.78–1.69 (m, 3H), 1.55–1.52 (m, 1H), 1.56–
1.50 (m, 1H), 1.49–1.40 (m, 1H); 13C NMR (125 MHz,
CDCl3): d 171.9, 138.7, 137.0, 130.3, 128.8, 128.3,
128.3, 128.1, 126.8, 72.7, 64.9, 57.6, 44.0, 33.8, 32.3,
25.4, 20.3; HRMS (FAB) [M+H]+ (C21H24NO2) calcd
322.1807, found 322.1804.
0.32 mmol 75%). Rf 0.45 (ethyl acetate/hexanes: 1/5);
25
½aꢁD ¼ ꢀ107:3 (c 1, CHCl3); 1H NMR (500 MHz,
3.5.6. (4R,9aR)-9a-Methyl-4-phenylhexahydropyrido[2,1-
c][1,4]oxazin-1-one 11a. Rf 0.45 (ethyl acetate/hexanes:
CDCl3): d 7.35–7.29 (m, 5H), 4.42–4.36 (m, 2H), 4.21–
4.17 (m, 1H), 2.41 (br, 2H), 2.13 (dd, J = 8.5, 13.0 Hz,
1H), 2.01 (m, 1H), 1.84–1.76 (m, 2H), 1.52–1.42 (m,
3H), 1.23 (m, 3H), 0.96 (t, J = 7.3 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d 172.4, 138.9, 128.9, 128.5, 128.3,
71.9, 62.9, 57.0, 44.2, 37.5, 29.7, 25.3, 20.3, 17.5, 14.6;
HRMS (FAB) [M+H]+ (C17H24NO2) calcd 274.1807,
found 274.1811.
25
1
1/5); ½aꢁD ¼ ꢀ50:3 (c 1, CHCl3); H NMR (500 MHz,
CDCl3): d 7.37–7.31 (m, 5H), 4.36 (dd, J = 3.5,
10.5 Hz, 1H), 4.25 (t, J = 10.5 Hz, 1H), 4.16 (dd,
J = 3.5, 10.6 Hz, 1H), 2.79 (dt, J = 3.0, 14.0 Hz, 1H),
2.57–2.54 (m, 1H), 2.16 (m, 1H), 1.75–1.69 (m, 2H),
1.66 (s, 3H), 1.63 (m, 1H), 1.46–1.41 (m, 1H), 1.05 (m,
1H); 13C NMR (125 MHz, CDCl3): d 174.6, 137.1,
128.9, 128.5, 128.3, 73.0, 61.1, 56.8, 43.2, 29.0, 22.6,
20.2, 18.9; HRMS (FAB) [M+H]+ (C15H20NO2) calcd
246.1494; found 246.1501.
3.5.2. (4R,9aS)-9a-Methyl-4-phenylhexahydropyrido[2,1-
c][1,4]oxazin-1-one 8a. Rf 0.43 (ethyl acetate/hexanes
25
1
1:5); ½aꢁD ¼ ꢀ119:9 (c 1, CHCl3); H NMR (500 MHz,
CDCl3): d 7.35–7.25 (m, 5H), 4.28 (t, J = 10.6 Hz,
1H), 4.23 (dd, J = 4.7, 10.6 Hz, 1H), 3.97 (dd, J = 4.7,
10.6 Hz, 1H), 2.40 (dt, J = 3.4, 11.9 Hz, 1H), 2.17 (dt,
J = 3.2, 11.9 Hz, 1H), 2.11–2.08 (m, 1H), 1.84 (dt,
J = 4.3, 13.1 Hz, 1H), 1.66–1.63 (m, 1H), 1.59–1.50
(m, 1H), 1.47–1.38 (m, 2H), 1.44 (s, 3H); 13C NMR
(125 MHz, CDCl3): d 173.7, 137.6, 128.8, 128.4, 128.4,
73.1, 60.3, 58.2, 43.7, 34.5, 29.7, 25.3, 19.9, 13.5; HRMS
(EI) [M]+ (C15H19NO2) calcd 245.1416, found 245.1416.
3.5.7. (4R,9aR)-9a-Ethyl-4-phenylhexahydropyrido[2,1-
c][1,4]oxazin-1-one 11b. Rf 0.41 (ethyl acetate/hexanes:
25
1
1/6); ½aꢁD ¼ ꢀ47:2 (c 1, CHCl3); H NMR (500 MHz,
CDCl3): d 7.36–7.29 (m, 5H), 4.39 (dd, J = 3.2,
10.6 Hz, 1H), 4.19 (t, J = 10.6 Hz, 1H), 4.10 (dd,
J = 3.2, 10.6 Hz, 1H), 2.65 (dt, J = 2.8, 15.0 Hz, 1H),
2.53 (dd, J = 1.9, 15.0 Hz, 1H), 2.31 (m, 1H), 2.17–
2.11 (m, 1H), 1.86 (m, 1H), 1.76–1.63 (m, 4H), 1.47–
1.36 (m, 1H), 1.02 (t, J = 7.3 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d 174.2, 137.4, 128.9, 128.5, 128.3,
73.1, 65.5, 56.4, 42.1, 29.5, 26.7, 20.6, 18.7, 8.9; HRMS
(FAB) [M+H]+ (C16H22NO2) calcd 260.1651; found
260.1653.
3.5.3. (4R,9aS)-9a-Ethyl-4-phenylhexahydropyrido[2,1-
c][1,4]oxazin-1-one 8b. Rf 0.45 (ethyl acetate/hexanes
25
1
1:5); ½aꢁD ¼ ꢀ91:2 (c 1, CHCl3); H NMR (500 MHz,
CDCl3): d 7.28–7.26 (m, 5H), 4.41 (t, J = 6.4 Hz, 1H),
4.39 (m, 1H), 4.18 (dd, J = 6.4, 8.4 Hz, 1H), 2.41 (t,
J = 5.4 Hz, 2H), 2.17–2.08 (m, 2H), 1.91–1.84 (m, 1H),
1.77 (dt, J = 4.0, 12.3 Hz, 1H), 1.56 (t, J = 4.5 Hz,
1H), 1.52–1.46 (m, 1H), 1.44–1.41 (m, 2H), 0.98 (t,
J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): d
172.2, 138.8, 128.8, 128.1, 127.9, 71.9, 63.2, 56.8, 44.1,
30.5, 25.3, 20.3, 20.0, 8.6; HRMS (FAB) [M+H]+
(C16H22NO2) calcd 260.1651, found 260.1651.
3.5.8. (4R,9aR)-9a-Propyl-4-phenylhexahydropyrido[2,1-
c][1,4]oxazin-1-one 11c. Rf 0.44 (ethyl acetate/hexanes:
25
1
1/6); ½aꢁD ¼ ꢀ49:1 (c 1, CHCl3); H NMR (500 MHz,
CDCl3): d 7.34–7.33 (m, 5H), 4.38 (dd, J = 2.7,
10.5 Hz, 1H), 4.19 (t, J = 10.5 Hz, 1H), 4.10 (dd,
J = 2.7, 10.5 Hz, 1H), 2.65 (dt, J = 2.0, 14.6 Hz, 1H),
2.53 (dt, J = 2.0, 14.6 Hz, 1H), 2.27 (dt, J = 3.7,
12.4 Hz, 1H), 2.13 (dt, J = 5.3, 12.9 Hz, 1H), 1.81 (dt,
J = 4.4, 12.6 Hz, 2H), 1.76–1.71 (m, 3H), 1.64 (m,
1H), 1.45–1.37 (m, 1H), 31–1.26 (m, 2H), 0.97 (t,
J = 7.1 Hz, 3H), 13C NMR (125 MHz, CDCl3): d
174.3, 137.4, 128.9, 128.5, 128.3, 73.1, 65.0, 56.4, 42.3,
3.5.4. (4R,9aS)-9a-Allyl-4-phenylhexahydropyrido[2,1-
c][1,4]oxazin-1-one 8d. Rf 0.41 (ethyl acetate/hexanes:
25
1
1/7); ½aꢁD ¼ ꢀ109:3 (c 1, CHCl3); H NMR (500 MHz,