500 cm3 two-necked flask and was heated at 140 ЊC under 0.1
mmHg for 2 h. While the flask was still hot, nitrogen gas was
introduced and the flask was cooled in an ice-bath. Dry THF
(150 cm3) was then added with stirring, and stirring was
continued for 2 h at room temperature. The resulting suspen-
sion was again cooled to 0 ЊC and Grignard reagent [freshly
prepared with 5-bromopent-1-ene (6.0 g, 40 mmol) and
magnesium turnings (0.97 g, 40 mmol)] was added. After this
mixture had been stirred for 1.5 h at 0 ЊC, a solution of crude
imine (R)-7 (20 mmol) in dry THF (50 cm3) was added dropwise
over a 10 min period and the mixture was warmed to room
temperature. After the reaction mixture had been stirred for
20 h, it was quenched with a small amount of saturated aq.
K2CO3. The resulting white precipitate was filtered off, and
the filtrate was evaporated under reduced pressure. The crude
product was purified by bulb-to-bulb distillation (bp 120 ЊC,
2 mmHg) to give the amine 8 (85%) as a colorless oil (Found:
C, 78.35; H, 10.71; N, 4.98. Calc. for C18H29NO: C, 78.49; H,
10.61; N, 5.09%); [α]D24 Ϫ78.6 (c 1.62 in EtOH); νmax(film)/cmϪ1
3360 (NH), 2940 (CH); δH(CDCl3) 0.77 (3 H, t, J 6.7, 9-H3),
1.17–1.48 (8 H, m, 4-, 5-, 7- and 8-H2), 1.69 (1 H, br, NH),
1.98–2.06 (2 H, m, 3-H2), 2.29–2.37 (1 H, m, 6-H), 3.35 (3 H, s,
OMe), 3.38–3.43 (2 H, m, 2Ј-H2), 4.00 (1 H, dd, J 5.5 and 7.3,
1Ј-H), 4.92–5.03 (2 H, m, 1-H2), 5.80 (1 H, ddt, J 6.7, 10.4 and
17.1, 2-H), 7.22–7.38 (5 H, m, Ph); m/z (CI, isobutane) 276
(Mϩ ϩ 1).
were added n-butanal (1.36 g, 18.90 mmol) and 3 Å molecular
sieves at 0 ЊC. The reaction mixture was stirred at room tem-
perature for 40 h, filtered through Celite, and evaporated under
reduced pressure to afford the crude product, which was purified
by distillation with a tube oven to give the oxazolidine 12 (5.6 g,
96%), bp 245 ЊC/4 mmHg (Found: C, 71.21; H, 7.99; N, 3.75.
Calc. for C22H29NO4: C, 71.13; H, 7.87; N, 3.77%); [α]D22 Ϫ59.33
(c 1.07 in EtOH); νmax(film)/cmϪ1 2830 (CH); δH(CDCl3) 0.93
(3 H, t, J 7.3, Me), 1.38–1.70 (4 H, m), 3.51 (1 H, dd, J 7.3 and
7.9, 5-H), 3.66 (6 H, s, OMe), 3.76 (2 H, s), 3.78 (3 H, s, OMe)
3.92 (1 H, dd, J 6.7 and 7.9, 5-H), 4.01 (1 H, dd, J 6.7 and 7.3,
4-H), 4.38 (1 H, dd, J 2.4 and 6.1, 2-H), 6.01 (2 H, s, ArH), 7.16–
7.41 (5 H, m, Ph); m/z (CI, isobutane) 372 (Mϩ ϩ 1).
(6R,1ЈR)-6-[N-(2Ј-Hydroxy-1Ј-phenylethyl)-2,4,6-trimethoxy-
benzylamino]non-1-ene 13
To a solution of (2R,4R)-12 (5.0 g, 13.5 mmol) in dry THF (20
cm3) was added dropwise Grignard reagent [freshly prepared
with 5-bromopent-1-ene (6.0 g, 40 mmol) and magnesium turn-
ings (0.97 g, 40 mmol)] at 0 ЊC. After the reaction mixture had
been stirred for 20 h at room temperature, it was quenched with
a small amount of saturated aq. K2CO3. The resulting white
precipitate was filtered off, and the filtrate was evaporated
under reduced pressure. The crude product was purified by
column chromatography on silica gel (CH2Cl2–MeOH, 99:1) to
give enol 13 (5.47 g, 92%) (Found: C, 73.48; H, 9.20; N, 3.04.
Calc. for C27H39NO4: C, 73.43; H, 8.90; N, 3.17%); [α]D24 Ϫ133.43
(c 1.05 in EtOH); νmax(film)/cmϪ1 3440 (OH), 2920 (CH);
δH(CDCl3) 0.54 (3 H, t, J 6.7, 9-H3), 0.66–1.67 (8 H, m, 4-, 5-,
7- and 8-H2), 1.92 (2 H, dt, J 6.7 and 7.7, 3-H2), 2.46 (1 H, m,
6-H), 3.36 (1 H, br, OH), 3.75–3.99 (5 H, m), 3.82 (3 H, s,
OMe), 3.83 (6 H, s, OMe), 4.90 (1 H, dd, J 1.8 and 10.4, 1-H),
4.93 (1 H, dd, J 1.8 and 17.1, 1-H), 5.77 (1 H, ddt, J 6.7, 10.4,
and 17.1, 2-H), 6.13 (2 H, s, ArH), 7.26–7.42 (5 H, m, Ph);
m/z (CI, isobutane) 442 (Mϩ ϩ 1).
(6S,1ЈR)-6-(2Ј-Methoxy-1Ј-phenylethylamino)nonan-2-one 9
Oxygen was bubbled into a solution of (6S,1ЈR)-8 (3.8 g, 14
mmol), palladium() chloride bisacetonitrile complex (0.6 g,
2.0 mmol) and cupric [copper()] chloride (1.8 g, 20 mmol) in
MeOH (100 cm3) at room temperature. After being stirred for
2 h, the reaction mixture was filtered, and evaporated under
reduced pressure. The residue was treated with benzene (100
cm3), water (100 cm3) and 28% aq. ammonia (20 cm3). The
organic layer was separated, dried over anhydrous Na2SO4,
evaporated under reduced pressure, and purified by column
chromatography on silica gel (CH2Cl2–MeOH, 98:2) to give
ketone 9 (2.9 g, 74%) (Found: C, 74.04; H, 10.11; N, 4.68. Calc.
for C18H29NO2: C, 74.18; H, 10.03; N, 4.81%); [α]D24 Ϫ49.0 (c
1.17 in EtOH); νmax(film)/cmϪ1 3450 (NH), 2930 (CH), 1720
(CO); δH(CDCl3) 0.78 (3 H, t, J 6.7, 9-H3), 1.20–1.63 (8 H, m,
4-, 5-, 7- and 8-H2), 1.84 (1 H, br, NH), 2.12 (3 H, s, 1-H3),
2.32–2.39 (1 H, m, 6-H), 2.39 (2 H, t, J 6.7, 3-H2), 3.35 (3 H,
s, OMe), 3.38–3.43 (2 H, m, 2Ј-H2), 3.99 (1 H, dd, J 4.9 and
7.9, 1Ј-H), 7.22–7.38 (5 H, m, Ph); m/z (CI, isobutane) 292
(Mϩ ϩ 1).
(6R,1ЈR)-6-[N-(2Ј-Hydroxy-1Ј-phenylethyl)-2,4,6-trimethoxy-
benzylamino]nonan-2-one 14
Oxygen was bubbled into a solution of (6R,1ЈR)-13 (5.0 g, 11.32
mmol), palladium chloride bisacetonitrile complex (0.3 g, 1.13
mmol) and cupric chloride (2.0 g, 14.71 mmol) in MeOH (100
cm3) at room temperature. After being stirred for 3 h, the reac-
tion mixture was filtered, and evaporated under reduced pres-
sure. The residue was treated with benzene (50 cm3), water (50
cm3) and ammonia water (10 cm3). The organic layer was separ-
ated, dried over anhydrous Na2SO4, evaporated under reduced
pressure and purified by column chromatography on silica gel
(CH2Cl2–MeOH, 98:2) to give ketone 14 (3.94 g, 76%) (Found:
C, 70.94; H, 8.76; N, 3.05. Calc. for C27H39NO5: C, 70.86; H,
8.59; N, 3.06%); [α]D24 Ϫ122.52 (c 1.04 in EtOH); νmax(film)/cmϪ1
3460 (OH), 2920 (CH), 1700 (CO); δH(CDCl3) 0.57 (3 H, t,
J 6.7, 9-H3), 0.67–1.74 (8 H, m, 4-, 5-, 7- and 8-H2), 2.06 (3 H, s,
1-H3), 2.19 (2 H, m, 3-H2), 2.43 (1 H, m, 6-H), 3.38 (1 H, m,
OH), 3.79–3.99 (5 H, m), 3.82 (3 H, s, OMe), 3.83 (6 H, s,
OMe), 6.15 (2 H, s, ArH), 7.27–7.41 (5 H, m, Ph); m/z (CI,
isobutane) 458 (Mϩ ϩ 1).
(2R,6S)-Dihydropinidine hydrochloride 10
To a solution of 9 (2.2 g, 7.6 mmol) in MeOH (40 cm3) were
added a catalytic amount of 10% palladium on carbon and 3%
HCl (15 cm3). The reaction mixture was stirred under hydrogen
(1 atm) at room temperature for 40 h. Then it was filtered
through Celite and evaporated under reduced pressure. The
residue was treated with distilled HCl and washed with diethyl
ether. The aqueous layer was evaporated under reduced pres-
sure to give the title compound 10 as colorless needles (0.97 g,
73%), mp 245 ЊC (from EtOH–EtOAc) (lit.,5a 245–246 ЊC); [α]D23
ϩ14.2 (c 1.05 in EtOH) {lit.,10 [α]D20 ϩ12.8 (c 1.07 in EtOH)};
νmax(KBr)/cmϪ1 2940, 2840, 2800, 2750, 1460; δH(CDCl3) 0.93
(3 H, t, J 7.3, Me), 1.24–1.98 (9 H, m), 1.58 (3 H, d, J 6.7, Me),
2.08–2.21 (1 H, m), 2.86–2.99 (1 H, m, 2-H), 3.03–3.15 (1 H, m,
6-H), 9.01 (1 H, br, NH), 9.34 (1 H, br, NH); m/z (EI) 141 (Mϩ),
140 (Mϩ Ϫ 1), 126.
(2S,6R)-Dihydropinidine hydrochloride 15
To a solution of (6R,1ЈR)-14 (2.0 g, 4.37 mmol) in MeOH
(20 cm3) were added a catalytic amount of 10% palladium on
carbon and 3% HCl (7 cm3). The reaction mixture was stirred
under hydrogen (1 atm) at room temperature for 40 h. Then it
was filtered through Celite and evaporated under reduced pres-
sure. The residue was treated with distilled HCl and washed
with diethyl ether. The aqueous layer was evaporated under
reduced pressure to give the title compound 15 as colorless
needles (0.63 g, 84%); [α]D24 Ϫ12.71 (c 1.14 in EtOH) {lit.,10 [α]D20
ϩ12.8 (c 1.07 in EtOH)}.
(2R,4R)-4-Phenyl-2-propyl-3-(2,4,6-trimethoxybenzyl)-1,3-
oxazolidine 12
To a solution of (R)-11 (5.0 g, 15.75 mmol) in CH2Cl2 (60 cm3)
J. Chem. Soc., Perkin Trans. 1, 1999, 2791–2794
2793