in THF, 0.69 mmol) and ethyl (a-bromomethyl)acrylate (134 mg,
(1R,9aR)-Diethyl 2,6,7,8,9,9a-hexahydro-1H-quinolizine-1,3-
0.69 mmol) in THF (3 mL) gave the crude product as a single
diastereomer (by H NMR spectroscopy). Purification by flash
dicarboxylate 22 and (1R,5S,11aR)-3-methyl-octahydro-1,5-
methanopyrido[1,2-a][1,5]diazocine-2,6-dione 15
1
chromatography with petrol–EtOAc (9 : 1) as eluent gave alkylated
amino ester (R,R,S)-20 (165 mg, 93%) as a colourless oil, [a]D
−10.7 (c 1.0 in CHCl3); RF(9 : 1 petrol–EtOAc) 0.25; IR (film):
A suspension of 20% Pd(OH)2 on C (20 mg, 0.02 mmol), a
50 : 50 mixture of hydroxylamines 21 (110 mg, 0.25 mmol) and
+
−
NH4 HCO2 (48 mg, 0.75 mmol) in EtOH (1 mL) was stirred
and heated at reflux under N2 for 16 h. After being allowed to
cool to rt, the solids were removed by filtration through Celite
and washed with CH2Cl2 (50 mL). Then, 2 M NH4OH(aq) (5 mL)
was added to the filtrate and the two layers were separated. The
aqueous layer was extracted with CH2Cl2 (3 × 10 mL) and the
combined organic extracts were dried (MgSO4) and evaporated
under reduced pressure to give the crude product. Purification
by flash chromatography with CH2Cl2–MeOH (50 : 1) and then
CH2Cl2–MeOH (9 : 1) as eluent gave quinolizidine 22 (24 mg,
34%) as a colourless oil, [a]D +94.4 (c 1.0 in CHCl3); RF(9 : 1
−1
1
=
1720 (C O) cm ; H NMR (400 MHz, CDCl3) d: 7.37 (br d,
J = 7.5 Hz, 2H), 7.30 (br t, J = 7.5, Hz, 2H), 7.22 (br t, J =
7.5, Hz, 1H), 6.16 (d, J = 1.0 Hz, 1H), 5.57 (d, J = 1.0 Hz, 1H),
4.28 (q, J = 6.5 Hz, 1H), 4.24–4.02 (m, 4H), 3.30 (ddd, J = 12.0,
7.0, 3.0 Hz, 1H), 2.84 (td, J = 7.0, 3.5 Hz, 1H), 2.77 (ddd, J =
13.0, 8.0, 3.5 Hz, 1H), 2.66 (br d, J = 14.5 Hz, 1H), 2.54–2.44
(m, 2H), 1.76–1.37 (m, 6H), 1.31 (d, J = 6.5 Hz, 3H), 1.24 (t, J =
7.0 Hz, 3H), 1.22 (t, J = 7.0 Hz, 3H); 13C NMR (100.6 MHz,
=
=
CDCl3) d: 173.9 (C O), 166.8 (C O), 145.0 (ipso-Ph), 138.5 (C),
127.9 (Ph), 127.6 (Ph), 126.6 (CH2), 126.4 (Ph), 60.6 (CH2), 60.1
(CH2), 58.2 (CH), 55.9 (CH), 45.6 (CH), 43.6 (CH2), 29.5 (CH2),
23.9 (CH2), 23.2 (CH2), 22.5 (CH2), 14.7 (Me), 14.2 (Me), 14.1
(Me); MS (CI, NH3) m/z 388 [(M + H)+, 100], 188 (40); HRMS
(CI, NH3) m/z [M + H]+ calcd for C23H33NO4, 388.2488; found,
388.2482.
=
=
CH2Cl2–MeOH) 0.75; IR (film): 3015, 1730 (C O), 1665 (C O),
−1
1
=
1620 (C C), 1220 cm ; H NMR (400 MHz, CDCl3) d: 7.31
(d, J = 2.0 Hz, 1H), 4.20 (q, J = 7.0 Hz, 2H), 4.15 (q, J =
7.0 Hz, 2H), 3.55–3.50 (m, 1H), 3.45–3.38 (m, 1H), 3.18 (td, J =
13.0, 3.0 Hz, 1H), 2.87 (dt, J = 12.0, 5.5 Hz, 1H), 2.62 (ddd,
J = 16.5, 5.5, 1.5 Hz, 1H), 2.40 (ddd, J = 16.5, 12.0, 2.0 Hz,
1H), 1.92–1.87 (m, 1H), 1.73–1.34 (m, 5H), 1.28 (t, J = 7.0 Hz,
3H), 1.27 (t, J = 7.0 Hz, 3H); 13C NMR (100.6 MHz, CDCl3)
(4R)-Diethyl 2-[(N-hydroxy-N-methylamino)methyl]-4-{(2R)-1-
[(1S)-1-phenylethyl]piperidin-2-yl}pentanedioate 21
=
=
d: 172.2 (C O), 168.4 (C O), 144.7 (CH), 94.9 (C), 60.7 (CH2),
59.2 (CH2), 55.7 (CH), 54.6 (CH2), 41.8 (CH), 26.5 (CH2), 25.8
(CH2), 24.6 (CH2), 19.0 (CH2), 14.7 (Me), 14.2 (Me); MS (CI,
NH3) m/z 282 [(M + H)+, 100]; HRMS (CI, NH3) m/z [M + H]+
calcd for C15H23N2O4, 282.1705; found, 282.1699 and bislactam 15
(27 mg, 48%) as a colourless oil, [a]D +41.8 (c 1.0 in CHCl3); RF(9 :
Et3N (14 lL, 0.1 mmol) was added dropwise to a stirred solution of
N-methylhydroxylamine hydrochloride (9 mg, 0.1 mmol) in THF
(2 mL) at rt under N2. After stirring for 10 min, a solution of
alkylated amino ester (R,R,S)-20 (40 mg, 0.1 mmol) was added
dropwise via a cannula and the resulting solution was stirred at rt
for 64 h. The solvent was evaporated under reduced pressure and
Et2O (5 mL) was added to the residue. The solids were removed by
filtration through a plug of silica and washed with Et2O (50 mL).
The solvent was evaporated under reduced pressure to give the
crude product. Purification by flash chromatography with petrol–
=
1 CH2Cl2–MeOH) 0.4; IR (film): 3015, 2940, 1730 (C O), 1635
−1
1
=
(C O), 1440, 1215 cm ; H NMR (400 MHz, CDCl3) d: 4.74
(ddd, J = 13.5, 4.0, 2.0 Hz, 1H), 3.51–3.40 (m, 2H), 3.38 (ddd, J =
12.0, 5.0, 3.0 Hz, 1H), 2.93 (s, 3H), 2.93–2.88 (m, 1H), 2.82–2.78
(m, 1H), 2.49 (td, J = 13.5, 3.5 Hz, 1H), 2.10–2.07 (m, 2H), 1.99–
1.92 (m, 1H), 1.87–1.83 (m, 1H), 1.73–1.68 (m, 1H), 1.40–1.20
13
=
(m, 3H); C NMR (100.6 MHz, CDCl3) d: 170.0 (C O), 168.1
1
EtOAc (3 : 1) as eluent gave a 50 : 50 mixture (by H NMR
=
(C O), 59.2 (CH), 52.8 (CH2), 42.2 (CH2), 41.7 (CH), 37.1 (CH),
spectroscopy) of hydroxylamines 21 (38 mg, 85%) as a colourless
34.0 (Me), 31.3 (CH2), 25.0 (CH2), 24.8 (CH2), 24.1 (CH2); MS
(CI, NH3) m/z 282 [(M + H)+, 100]; HRMS (CI, NH3) m/z [M +
H]+ calcd for C12H18N2O2, 223.1447; found, 223.1448.
−1
=
oil, RF(3 : 1 petrol–EtOAc) 0.2; IR (film): 1730 (C O) cm ;
1H NMR (400 MHz, CDCl3) d: 7.41–7.34 (m, 2H), 7.33–7.25
(m, 2H), 7.24–7.17 (m, 1H), 6.28 (br s, 0.5H), 5.79 (br s, 0.5H),
4.28–3.97 (m, 4.5H), 3.85 (dq, J = 11.0, 7.5 Hz, 0.5H), 3.20–
3.12 (m, 0.5H), 3.08–3.03 (m, 0.5H), 2.88–2.80 (m, 2H), 2.73–
2.55 (m, 3H), 2.60 (s, 1.5H), 2.52 (s, 1.5H), 2.42–2.36 (m, 0.5H),
2.32–2.25 (m, 0.5H), 2.04–1.85 (m, 2H), 1.68–1.58 (m, 1H), 1.50–
(1S,2S,9S)-11-Methyl-7,11-diazatricyclo[7.3.1.02,7]tridecane,
(−)-sparteine surrogate
1.05 (m, 11H), 1.20 (t, J = 7.5 Hz, 1.5H), 1.07 (t, J = 7.5 Hz,
LiAlH4 (77 mg, 2.03 mmol) was added in one portion to a stirred
so◦lution of bislactam 15 (75 mg, 0.34 mmol) in THF (1.5 mL) at
0 C under N2. The resulting suspension was stirred and heated
at reflux for 16 h. After cooling to rt, Et2O (1 mL) was added
and solid Na2SO4·H2O was added portionwise until effervescence
ceased. The resulting mixture was stirred at rt for 30 min. The
solids were removed by filtration through Celite and washed with
9 : 1 CH2Cl2–MeOH (30 mL). The filtrate was dried (MgSO4) and
the solvent evaporated under reduced pressure to give the crude
product as a yellow oil. Purification by Kugelrohr distillation gave
(−)-sparteine surrogate (44 mg, 68%) as a pale yellow oil, bp 110–
13
=
1.5H); C NMR (100.6 MHz, CDCl3) d: 175.0 (C O), 174.8
=
=
=
(C O), 174.7 (C O), 174.3 (C O), 144.5 (ipso-Ph), 144.3 (ipso-
Ph), 128.0 (Ph), 127.8 (Ph), 127.6 (Ph), 127.4 (Ph), 126.5 (Ph),
126.3 (Ph), 63.8 (CH2), 63.0 (CH2), 60.5 (CH2), 60.41 (CH2),
60.38 (CH2), 60.3 (CH2), 58.8 (CH), 55.4 (CH), 54.7 (CH), 48.78
(CH), 48.76 (CH), 44.6 (CH), 44.4 (CH), 44.2 (CH2), 44.0 (CH2),
42.8 (CH2), 42.7 (CH2), 26.5 (CH2), 25.5 (CH2), 25.3 (CH2), 24.6
(CH2), 24.3 (CH2), 23.8 (CH2), 23.5 (CH2), 23.0 (CH2), 14.2 (Me),
14.15 (Me), 14.1 (Me), 14.0 (Me), 13.9 (Me), 13.1 (Me); MS
(CI, NH3) m/z 435 [(M + H)+, 100], 188 (65), 389 (30); HRMS
(CI, NH3) m/z [M + H]+ calcd for C24H38N2O5, 435.2859; found,
435.2856.
◦
◦
115 C/0.3 mmHg (lit.,27b 95–110 C/0.8 mmHg); [a]D −29.6 (c
1.0 in EtOH) (lit.,27b [a]D +26.5 (c 1.0 in EtOH) for (+)-sparteine
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 3614–3622 | 3621
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