Bates and Lu
JOCArticle
refluxing solution of piperidines 12 (56 mg, 0.18 mmol) and 3-
buten-2-one (53 μL, 0.54 mmol) in CH2Cl2 (2 mL) in four
portions via syringe over 1 h. The mixture was heated at reflux
overnight and then concentrated under reduced pressure. The
residue was purified by flash chromatography (EtOAc/
hexane = 2: 8) to provide 14 (51 mg, 80%) as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 6.73 (1H, dt, J = 15.8, 7.7 Hz),
6.07 (1H, d, J = 15.8 Hz), 4.25 (2H, brs), 3.54-3.51 (1H, m),
2.44-2.38 (2H, m), 2.22 (3H, s), 1.76-1.33 (21H, m), 0.91 (3H, t,
J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 198.4, 155.4, 144.9,
132.9, 80.2, 69.6, 49.5, 47.5, 44.0, 40.0, 37.8, 28.4 (3C), 27.4, 27.0,
26.1, 18.8, 14.0, 13.7; IR (neat) 3447, 2957, 2932, 2860, 1655,
1643 cm-1; MS (m/z) 376 [M þ Na]þ; HRMS m/z calcd for
C20H35O4NNa [M þ Na]þ 376.2464, found 376.2452.
(500 MHz, CDCl3) δ 5.49 (1H, brs), 4.46 (1H, t, J = 5.5 Hz),
4.22 (1H, tdd, J = 9.8, 5.0, 2.8 Hz), 3.63 (2H, qd, J = 7.1, 9.3
Hz), 3.51-3.40 (3H, m), 1.96 (1H, ddt, J = 13.5, 4.5, 1.5 Hz),
1.70-1.34 (11H, m), 1.20 (6H, t, J = 7.1 Hz), 0.93 (3H, t, J =
7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 154.8, 102.5, 76.8, 61.2,
61.1, 50.8, 37.2, 36.0, 33.3, 33.1, 20.0, 17.9, 15.3(2C), 13.8; IR
(neat) 2961, 2932, 2874, 2243, 1697 cm-1; MS (m/z) 310 [M þ
Na]þ; HRMS m/z calcd for C15H29O4NNa [M þ Na]þ 310.1994,
found 310.1989.
(3R,4aS,8R)-8-Ethoxyhexahydro-3-propylpyrido[1,2-c][1,3]oxa-
zin-1(3H)-one 17. p-TsOH (0.48 g, 2.39 mmol) was added to a
solution of compound 16 (133 mg, 0.48 mmol) in EtOH (5 mL)
at room temperature. The mixture was stirred at room tempera-
ture for 4 h. Saturated aqueous NaHCO3 (5 mL) was added,
and the mixture was extracted with CH2Cl2 (3 ꢀ 5 mL). The
combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered through Celite, and concentrated in
vacuo. The residue was purified by flash chromatography
(EtOAc/hexane = 1:9) to provide trans-17 (0.11 g, 91%) as a
(2S,6R)-tert-Butyl 2-((R)-2-Hydroxypentyl)-6-(4-oxopentyl)-
piperidine-1-carboxylate 15.
A suspension of alkenes 14
(51 mg, 0.14 mmol) and palladium on carbon (10%) (8 mg,
5 mol %) in MeOH (5 mL) was stirred at room temperature for
2 h under H2 (1 atm). The reaction mixture was filtered through
Celite, washing with MeOH (5 ꢀ 3 mL). The filtrate was con-
centrated in vacuo. The residue was purified by flash chroma-
tography (EtOAc/hexane = 2:8) to afford cis-15 (35 mg, 77%)
single isomer and as a colorless solid: mp 57-59 °C; [R]23.6
D
þ30.0 (c 1.7, CHCl3); 1H NMR (300 MHz, CDCl3) δ 5.71 (1H,
br), 4.14-4.07 (1H, m), 3.56-3.39 (3H, m), 2.07-1.42 (12H, m),
1.18 (3H, t, J = 7.0 Hz), 0.93 (3H, t, J = 7.0 Hz); 13C NMR
(75 MHz, CDCl3) δ 154.1, 80.3, 75.0, 62.4, 49.1, 37.0, 35.3, 33.1,
29.9, 17.9, 17.6, 15.1, 13.9; IR (neat) 2957, 2936, 2874, 1694,
1422 cm-1; MS (m/z) 264 [M þ Na]þ; HRMS m/z calcd for
C13H23O3NNa [M þ Na]þ 264.1576, found 264.1567.
and trans-15 (4 mg, 8%) as colorless oils. cis-15: [R]24 -27.1
D
1
(c 1.6, CHCl3); H NMR (400 MHz, CDCl3) δ 4.18 (1H, brs),
4.04 (1H, brs), 3.51 (1H, brs), 2.46-2.43 (2H, m), 2.12 (3H, s),
1.55-1.35 (25H, m), 0.91 (3H, t, J = 6.8 Hz); 13C NMR (125
MHz, CDCl3) δ 208.6, 155.9, 79.9, 69.9, 50.4, 47.8, 44.3, 43.4,
40.0, 34.0, 29.9, 29.3, 28.4 (3C), 27.4, 21.3, 18.9, 14.1, 13.9; IR
(neat) 3447, 2957, 2932, 2860, 1655, 1643 cm-1; MS (m/z) 378 [M
þ Na]þ; HRMS m/z calcd for C20H37O4NNa [M þ Na]þ
378.2620, found 378.2615.
(3R,4aS,8S)-8-Allylhexahydro-3-propylpyrido[1,2-c][1,3]oxa-
zin-1(3H)-one 13b. To a solution of N,O-acetal 17 (48 mg,
0.21 mmol) and allyltrimethylsilane (0.10 mL, 0.63 mmol) in
CH2Cl2 (5 mL) was added TiCl4 (0.63 mmol, 0.63 mL of 1 M
solution in toluene) via syringe at -78 °C. After being stirred at
-78 °C for 0.5 h, the reaction mixture was quenched at this
temperature with saturated NaHCO3 and extracted with
CH2Cl2 (3 ꢀ 5 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered through
Celite, and concentrated in vacuo to afford the crude product.
The crude product was purified by flash chromatography
(EtOAc/hexane = 2: 8) to provide trans-13b (44 mg, 89%) as
trans-15. 1H NMR (500 MHz, CDCl3) δ 3.92-3.89 (1H, brs),
3.72-3.68 (1H, brs), 3.59-3.56 (1H, brs), 2.48-2.44 (2H, m),
2.14 (3H, s), 1.81-1.76 (2H, m), 1.73-1.70 (2H, m), 1.65-1.33
(12H, m), 1.46 (9H, s), 0.91 (3H, t, J = 7.0 Hz); 13C NMR
(125 MHz, CDCl3) δ 208.8, 155.9, 79.9, 70.0, 51.8, 49.5, 44.1,
43.4, 40.1, 33.6, 29.9, 28.5 (3C), 25.2, 23.6, 21.2, 18.9, 14.1, 13.5.
(2R,3aS,6aR,9aS)-Decahydro-9a-methyl-2-propyl-2H-[1,3]oxa-
zino[2,3,4-de]quinolizine 2. Trifluoroacetic acid (0.46 mL) was
added to a solution of compound 15 (23 mg, 0.062 mmol) in
CH2Cl2 (4 mL) at 0 °C. The reaction mixture was warmed to
room temperature and stirred for 2 h. The volatiles were
evaporated, and the residue was partitioned between aqueous
NaHCO3 and CH2Cl2. The aqueous lawyer was extracted
with CH2Cl2 (3 ꢀ 5 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered
through Celite, and concentrated in vacuo to afford the crude
product which was purified by flash chromatography (MeOH/
CH2Cl2 = 1: 9) to give product 2 (13 mg, 90%) as a colorless oil:
a single isomer and as a colorless oil: [R]24.4 þ6.9 (c 2.0,
D
1
CHCl3); H NMR (500 MHz, CDCl3) δ 5.80-5.73 (1H, m),
5.04 (1H, d, J = 17.0 Hz), 5.03 (1H, brd, J = 9.5 Hz), 4.70-4.66
(1H, m), 4.03 (1H, tt, J = 5.2, 5.2 Hz), 3.37 (1H, tdd, J = 11.4,
5.2, 2.9 Hz), 2.44 (1H, dt, J = 13.8, 8.3 Hz), 2.24 (1H, dt, J =
13.8, 6.8 Hz), 1.99 (1H, ddd, J = 13.8, 5.2, 1.5 Hz), 1.79-1.76
(1H, m), 1.66-1.12 (10H, m), 0.92 (3H, t, J = 7.2 Hz); 13C NMR
(125 MHz, CDCl3) δ 154.0, 135.3, 117.0, 74.2, 49.7, 49.3, 36.8,
35.7, 34.8, 33.3, 27.0, 18.1, 17.8, 13.8; IR (neat) 2957, 2934, 2872,
1687, 1427 cm-1; MS (m/z) 237 [M]þ; HRMS m/z calcd for
C14H23O2NNa [M þ Na]þ 260.1623, found 260.1618.
[R]24 þ6.0 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3) δ
D
3.79-3.76 (1H, m), 2.51-2.47 (1H, m), 2.15-2.10 (1H, m),
1.55-1.35 (21H, m), 0.88 (3H, t, J = 7.0 Hz); 13C NMR (125
MHz, CDCl3) δ 86.5, 67.8, 55.2, 51.9, 39.6, 39.2, 38.6, 34.4, 34.2,
33.8, 23.5, 20.8, 18.4, 14.1, 11.6; IR (neat) 2930, 2868,
2799 cm-1; MS (m/z) 238 [M þ H]þ; HRMS m/z calcd for
C15H28ON [M þ H]þ 238.2171, found 238.2164.
(3R,4aS,8S)-Hexahydro-8-((E)-4-oxopent-2-enyl)-3-propylp-
yrido[1,2-c][1,3]oxazin-1(3H)-one 18. A solution of Grubbs II
catalyst (11 mg, 5 mol %) in CH2Cl2 (2 mL) was added to a
refluxing solution of compound 13b (60 mg, 0.25 mmol) and 3-
buten-2-one (74 μL, 0.76 mmol) in CH2Cl2 (2 mL) in four
portions via syringe over 1 h. The mixture was heated at reflux
overnight and concentrated under reduced pressure. The residue
was purified by flash chromatography (EtOAc/hexane = 3:7) to
(4S,6R)-4-(4,4-Diethoxybutyl)-6-propyl-1,3-oxazinan-2-one 16.
tBuOK (83.0 mg, 7.38 mmol) was added to a solution of
compound 11 (178 mg, 4.92 mmol) in THF (7 mL) at 0 °C.
The mixture was allowed to warm to room temperature, and it
was stirred at room temperature for 4 h. The mixture was
quenched with saturated NH4Cl solution and extracted with
EtOAc (3 ꢀ 5 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered through
Celite, and concentrated in vacuo to afford the crude product.
The crude product was purified by flash chromatography
(EtOAc/hexane = 3: 7) to provide cyclic carbamate 16 (133
mg, 93%) as a colorless oil: [R]24D þ5.7 (c 1.3, CHCl3); 1H NMR
provide trans-18 (68 mg, 96%) as a single isomer and as a
1
colorless oil: [R]24 -2.6 (c 1.5, CHCl3); H NMR (300 MHz,
D
CDCl3) δ 6.74 (1H, ddd, J = 15.7, 8.7, 6.5 Hz), 6.02 (1H, d,
J = 15.7 Hz), 4.84-4.78 (1H, m), 4.01-3.94 (1H, m), 3.34 (1H,
tdd, J = 11.3, 5.0, 2.9 Hz), 2.63 (1H, dt, J = 13.9, 8.7 Hz), 2.24
(1H, dt, J = 13.9, 6.5 Hz), 2.24 (3H, s), 1.99 (1H, ddd, J = 11.2,
5.2, 1.5 Hz), 1.82-1.12 (11H, m), 0.89 (3H, t, J = 7.2 Hz); 13
C
NMR (75 MHz, CDCl3) δ 198.8, 153.9, 144.7, 133.7, 74.6, 49.6,
49.4, 36.8, 35.5, 33.9, 33.1, 27.5, 26.2, 18.1, 17.8, 13.7; IR (neat)
2957, 2936, 2874, 1674, 1429 cm-1; MS (m/z) 302 [M þ Na]þ;
9464 J. Org. Chem. Vol. 74, No. 24, 2009