Notes
J . Org. Chem., Vol. 62, No. 3, 1997 747
solution was cooled to -92 °C, boron trifluoride etherate (4.43
mL, 36 mmol) was added, and the solution was stirred for 15
min. An ether solution of pent-4-enylmagnesium bromide (2 M;
18 mL, 36 mmol) was added dropwise to the cooled toluene
solution over 30 min. After addition the solution was stirred
for 30 min at -92 °C followed by the addition of water (1 mL).
The mixture was allowed to warm to rt, and the solvent was
removed under reduced pressure. The residue was partitioned
between CH2Cl2 (50 mL) and water (50 mL). The layers were
separated, and the aqueous layer was washed with further
portions of CH2Cl2 (2 × 50 mL). The combined organic extracts
were washed with brine and then dried (MgSO4), filtered, and
evaporated. Column chromatography of the residue on silica
gel (ether-petroleum ether 1:20) gave the title compound (94%,
95% de) as a colorless oil: [R]D -61.9° (c ) 0.62, CH2Cl2); IR
Sch em e 2
For the preparation of (+)-pseudoconhydrine, the
enantiomeric enecarbamate (S)-7, prepared from the
ROPHy oxime (R)-4 in an identical manner was con-
verted into the â-hydroxypiperidine 8 (58%) by hydrobo-
ration under similar conditions to those described by
Oppolzer.3c The hydroxypiperidine 8 was formed as a 2:1
mixture of diastereomers with the trans-isomer predomi-
nating as expected on the basis of the literature prece-
dent. Hydrogenolysis of the benzyloxycarbonyl group
gave (+)-pseudoconhydrine in excellent yield, mp 102-
(film) 2958, 2933, 1641, 1455, 910 cm-1 1H NMR (250 MHz,
;
CDCl3) δ 7.27 (m, 5H), 5.78 (m, 1H), 5.04 (br s, 1H), 4.96 (m,
2H), 4.52 (dd, 1H, J ) 5.6, 7.5 Hz), 2.79 (m, 1H), 2.04 (m, 2H),
1.54 (m, 12H), 0.91 (t, 3H, J ) 7.2 Hz), 0.85 (t, 3H, J ) 7.1 Hz);
13C NMR (62.9 MHz, CDCl3) δ 143.4, 138.9, 128.2, 127.2, 126.5,
114.3, 85.1, 60.0, 38.7, 34.0, 33.9, 31.7 (2 carbons), 25.0, 19.2,
14.2, 14.0; LRMS EI m/z (%) 157 (12), 133 (54), 114 (21), 91 (100);
HRMS calcd for C19H31NO 289.2405, found 289.2404.
103 °C, [R]20 +17.4° (c ) 0.62, CHCl3) (lit.,3e mp 102-
D
104 °C, [R]25 +11.1° (c ) 1, EtOH)) (Scheme 2).
D
(R)-(-)-N-(Ben zyloxyca r bon yl)-6-n on -1-en yla m in e (6).
Zinc dust (28.5 g, 443 mmol) was added to a solution of chiral
hydroxylamine 5 (3.2 g, 11.1 mmol) in acetic acid and water (20
mL, 1:1). The mixture was placed in a sonic bath at 40 °C for
2 h. The solution was filtered, ether (50 mL) and water (50 mL)
were added, the layers were separated, and the aqueous layer
was washed with further portions of ether and CH2Cl2. The
combined organic extracts were evaporated, and THF/water (100
mL, 1:1) was added to the residue. Solid Na2CO3 (1.27 g, 12
mmol) was added, the mixture was cooled to 0 °C, benzyl
chloroformate (1.6 mL, 11.1 mmol) was then added dropwise,
and the mixture was allowed to warm to rt and was stirred for
2 h. The THF was removed in vacuo, ether (50 mL) was added,
the layers were separated, and the aqueous layer was washed
with further portions of ether. The combined organic extracts
were dried (MgSO4), filtered, and evaporated. Column chro-
matograpy of the residue on silica gel (ether-petroleum ether
1:6) gave the title compound (87%) as a colorless solid: mp 71-
73 °C; [R]D -1.5° (c ) 1, CH2Cl2); IR (Nujol) 3312, 2925, 1687,
Exp er im en ta l Section
Gen er a l. General experimental details are given in ref 4.
Gen er a l Meth od for Alk oxyp h th a lim id es. Diethyl azodi-
carboxylate (6.4 mL, 40.4 mmol) was added to a solution of
N-hydroxyphthalimide (6 g, 37 mmol), triphenylphosphine (9.63
g, 37 mmol) and the substituted benzyl alcohol (37 mmol), in
THF (200 mL) at 0 °C. The resulting solution was warmed to
50 °C and stirred for 3 days. The solution was evaporated, and
ether (200 mL) and saturated Na2CO3 solution (200 mL) were
added and the layers separated. The ether layer was washed
with further portions of Na2CO3 solution (2 × 100 mL) which
were combined and back extracted with ether (2 × 100 mL). The
combined ether portions were evaporated, and the residue was
purified by column chromatography on silica gel with ether-
petroleum ether as eluent.
(S)-(-)-N-(1-P h en ylbu toxy)ph th alim ide (3). Obtained from
the Mitsunobu reaction of (R)-(+)-1-phenylbutanol with N-
hydroxyphthalimide (81%), >96% ee, as determined by NMR in
the presence of (-)-TFAE, as a crystalline solid: mp 80-81 °C;
[R]D -185.1° (c ) 2, CH2Cl2); IR (Nujol) 2922, 1789, 1727, 698
1547, 1462 cm-1 1H NMR (250 MHz, CDCl3) δ 7.32 (m, 5H),
;
5.70 (m, 1H), 5.08 (s, 2H), 4.95 (m, 2H), 4.50 (br d, 1H, J ) 9
Hz), 3.63 (br s, 1H), 2.04 (m, 2H), 1.42 (m, 8H), 0.90 (br t, 3H,
J ) 6.9 Hz); 13C NMR (62.9 MHz, CDCl3) δ 156.2, 138.5, 136.4,
128.4, 128.1, 128.0, 114.6, 66.4, 50.9, 37.6, 34.8, 33.5, 25.0, 18.9,
13.9; LRMS EI m/z (%) 232 (10), 162 (18), 91 (100); HRMS calcd
for C17H25NO2 275.1885, found 275.1892.
cm-1; H NMR (250 MHz, CDCl3) δ 7.70 (m, 4H), 7.45 (m, 2H),
1
7.29 (m, 3H), 5.34 (t, 1H, J ) 7.0 Hz), 2.16 (m, 1H), 1.91 (m,
1H), 1.47 (m, 2H), 0.97 (t, 3H, J ) 7.4 Hz); 13C NMR (62.9 MHz,
CDCl3) δ 163.8, 137.9, 134.1, 128.8, 128.8, 128.2, 128.0, 123.2,
89.0, 36.8, 18.9, 13.8; LRMS EI m/z (%) 163 (3), 133 (52), 117
(8), 104 (9), 91 (100), 76 (11); HRMS calcd for C18H17NO3
295.1208, found 295.1211.
(R)-(-)-1-(Ben zyloxyca r bon yl)-1,2,3,4-tetr a h yd r o-2-p r o-
p ylp yr id in e (7). Osmium tetraoxide (1 mol %, 14 mg, 0.06
mmol) was added to a solution of the alkene 6 (1.65 g, 6 mmol)
in THF/water (40 mL, 3:1), and the mixture was stirred at rt
for 5 min. The solution changed from colorless to brown, and
sodium periodate (2.35 g, 11 mmol) was then added portionwise
over 20 min. The reaction mixture was stirred for a further 20
min. Water (30 mL) and ether (50 mL) were added , the ether
layer was separated, and the aqueous layer was washed with
further portions of ether (4 × 30 mL). The combined organic
extracts were dried (MgSO4), filtered, and evaporated. Column
chromatograpy of the residue on silica gel (CH2Cl2) gave the title
compound (52%) as a colorless oil: [R]D -69.2° (c ) 0.5, CH2Cl2);
IR (film) 2958, 2933, 1705, 1416, 1327 cm-1; 1H NMR (250 MHz,
CDCl3) major rotamer δ 7.25 (m, 5H), 6.67 (br d, 1H, J ) 8 Hz),
5.11 (br s, 2H), 4.76 (br m, 1H), 4.26 (br m, 1H), 2.01-1.24 (m,
8H), 0.83 (br t, 3H), minor rotamer δ 6.75 (br d, 1H, J ) 8 Hz),
4.80 (br m, 1H), 4.18 (br m, 1H); 13C NMR (62.9 MHz, CDCl3)
both rotamers δ 153.4, 136.9, 128.9, 128.4, 128.4, 128.0, 124.0,
106.3, 67.7, 50.7, 33.1, 24.4, 19.5, 18.0, 14.4; LRMS EI m/z (%)
259 (M+, 9), 172 (20), 91 (100); HRMS calcd for C16H21NO2
259.1572, found 259.1579.
Gen er a l Meth od for O-Alk yloxim es. The N-alkoxyphthal-
imide (3.31 mmol) and EtOH (10 mL) were added to a round
bottomed flask, and the suspension was heated until the
phthalimide dissolved. Hydrazine hydrate (0.18 mL, 3.64 mmol)
was added at this elevated temperature, and the solution was
allowed to cool to rt. The aldehyde (0.37 g, 3.5 mmol) was added
and the mixture stirred overnight. The solvent was evaporated
and CCl4 (30 mL) and MgSO4 were added to the residue. The
resulting suspension was filtered, the filtrate evaporated, and
the residue purified by column chromatography (5% ether-
petroleum ether).
(S)-(-)-O-(1-P h en ylbu toxy)bu tyr a ld oxim e (4). Obtained
from the cleavage of (S)-(-)-N-(1-phenylbutoxy)phthalimide (3)
and subsequent condensation of the hydroxylamine with bu-
tyraldehyde (66%) as a colorless oil: [R]D -4.6° (c ) 0.78,
CH2Cl2); IR (film) 2959, 2934, 1454, 933 cm-1 1H NMR (250
;
MHz, CDCl3) δ 7.42 (t, 1H, J ) 6.2 Hz), 7.31 (m, 5H), 5.02 (t,
1H, J ) 6.8 Hz), 2.10 (dt, 2H, J ) 7.0, 14.2 Hz), 1.90 (m, 1H),
1.70 (m, 1H), 1.40 (m, 4H), 0.91 (t, 3H, J ) 7.3 Hz), 0.87 (t, 3H,
J ) 7.4 Hz); 13C NMR (62.9 MHz, CDCl3) δ 151.0, 142.9, 128.1,
127.1, 126.6, 84.4, 38.4, 31.3, 20.1, 18.8, 13.9, 13.4; LRMS EI
m/z (%) 220 (MH+, 100), 178 (74), 133 (96), 91 (94), 43 (36);
HRMS calcd for C14H21NO 219.1623, found 219.1626.
(6R,1′S)-(-)-N-(1-P h en ylbu toxy)-6-n on -1-en ylam in e 5. (S)-
(-)-O-(1-Phenylbutoxy)butyraldoxime (4) (2.62 g, 12 mmol) was
dissolved in dry toluene (40 mL) under nitrogen. The resulting
(R)-(-)-2-P r op ylp ip er id in e (con iin e) 1 a n d Con iin e Hy-
d r och lor id e 1‚HCl. Palladium on charcoal (10%; 70 mg) was
added to a solution of tetrahydropyridine 7 (1.68 g, 6.5 mmol)
in MeOH (20 mL), and the mixture was hydrogenated (41 psi
H2) for 12 h. The solution was filtered through Celite and half
the filtrate evaporated to give the title compound (0.4 g, 97%)
as a colorless oil: [R]D -8.1° (c ) 2, CHCl3) (lit.,2b [R]D -7.9° (c )