Enantiopure N-Acyldihydropyridones
J . Org. Chem., Vol. 62, No. 23, 1997 8185
doublets due to rotamers, 18 H, J ) 7.6 Hz); 13C NMR(CDCl3,
75 MHz) δ 196.9, 152.7 and 152.1 (doublet due to rotamers),
147.4, 128.0, 125.0, 110.1, 78.1, 62.1, 51.2 and 50.9 (doublet
due to rotamers), 40.2, 39.3, 33.4, 30.9, 28.5, 26.8, 25.8, 24.6,
21.3, 18.8, 18.7, and 11.0; IR (KBr) 3434, 3088, 3022, 1717,
1658 cm-1. Anal. Calcd for C33H53NO4Si: C, 71.30; H, 9.61;
N, 2.52. Found: C, 71.36; H, 9.58; N, 2.48.
methyl iodide (1.70 mL, 27.3 mmol) was added dropwise.
Stirring was continued for 2 h at -78 °C, the reaction mixture
was slowly warmed to -10 °C and was then stored in a freezer
overnight (-5 to -10 °C). After warming to rt, 25 mL of water
was added, and the crude mixture was extracted with diethyl
ether. The combined organic extracts were dried over anhy-
drous K2CO3 for 15 min (drying over K2CO3 for longer times
may cause epimerization at C-3). Filtration and concentration
in vacuo gave 3.18 g of the crude product. Purification by
radial PLC (silica gel, 10-30% EtOAc/hexanes) yielded 2.82
(-)-(2S )-2-(3′-H y d r o x y p r o p y l)-2,3-d ih y d r o -4-p y r i-
d on e (8). To a stirred solution of 7 (4.30 g, 7.74 mmol) in 20
mL of MeOH was added sodium methoxide (7.0 mL, 30.9
mmol, 4.37 M (25%) in MeOH). After refluxing for 3.5 h, and
cooling to rt, aqueous HCl (16.9 mL, 46.4 mmol, 2.74 M (10%))
was added. The mixture was stirred at rt for 15 min, and then
the methanol was removed in vacuo (0 °C). An aqueous
workup was avoided by adding THF and drying the mixture
with anhydrous K2CO3. Filtration and concentration yielded
3.56 g of the crude product. Purification by radial PLC (silica
gel, 10% MeOH/EtOAc/1% TEA) gave 3.25 g (96%) of the chiral
auxiliary ((+)-TCC) and 1.064 g (89%) of the desired 2,3-
dihydro-4-pyridone 8 as a white semisolid: [R]27D -430 (c 0.30,
MeOH); 1H NMR (CDCl3 300 MHz) δ 7.16 (t, 1 H, J ) 6.9 Hz),
5.35 (br s, 1 H), 5.02 (d, 1 H, J ) 7.3 Hz), 3.60-3.72 (m, 3 H),
2.30-2.51 (m, 2 H), 1.18-1.82 (series of m, 5 H); 13C NMR
(CDCl3, 75 MHz) δ 193.2, 151.4, 98.6, 62.3, 53.2, 42.1, 31.0,
g (96%) of the desired 2,3-dihydropyridone 11 as a clear oil:
1
[R]27.5 +29.7 (c 0.385, CHCl3); H NMR (CDCl3, 300 MHz) δ
D
7.72 (br s, 1 H), 7.39 (s, 5 H), 5.28 (shoulder at 5.24) (s, 3 H),
4.32 (br s, 1 H), 3.46 (br s, 2 H), 2.38 (apparent q, 1 H, J ) 6.7
and 7.2 Hz), 1.55-1.95 (m, 4 H, J ) 6.6 and 7.1 Hz), 1.20 (d,
3 H, J ) 7.3 Hz); 13C NMR (CDCl3, 75 MHz) δ 196.8, 152.9,
139.9, 134.7, 128.5, 128.2, 105.2, 68.9, 58.6, 44.0, 43.8, 28.6,
28.2, 16.7; IR (NaCl, neat): 3090, 3066, 3034, 1726, 1668, 1602
cm-1. Anal. Calcd for C17H20NO3Cl: C, 63.45; H, 6.26; N, 4.35.
Found: C, 63.39; H, 6.27; N, 4.38.
1-Br om o-4-(ben zyloxy)bu ta n e.16
Sodium hydroxide (20.0
g, 505 mmol) was carefully added to 40 mL of deionized water
at 0 °C. To the solution was added benzyl alcohol (10.35 mL,
100 mmol), 1,4-dibromobutane (59.7 mL, 500 mmol), and
tetrabutylammonium hydrogen sulfate (1.70 g, 5.0 mmol). The
reaction mixture was stirred at rt overnight, poured into 500
mL of H2O, and was extracted with hexanes. The organic
extracts were washed with brine, dried over anhydrous K2-
CO3, and concentrated in vacuo. The crude product was
purified by distillation (bp 101-105 °C, 0.40 mmHg) to yield
20.72 g (85%) of the desired product [67.2 g of 1,4-dibromobu-
tane was recovered (bp 31-41 °C, 0.35-0.5 mmHg)]: 1H NMR
(CDCl3, 300 MHz) δ 7.20-7.45 (m, 5 H), 4.50 (s, 2 H), 3.51 (t,
2 H, J ) 6.2 Hz), 3.44 (t, 2 H, J ) 6.8 Hz), 1.98 (quintet, 2 H,
J ) 7.9 Hz), 1.76 (quintet, 2 H, J ) 6.0 Hz).
(-)-(2S,3S,6R)-1-[(ben zyloxy)ca r bon yl]-2-(3′-ch lor op r o-
p yl)-3-m eth yl-6-[4′-(ben zyloxy)bu tyl]-4-p ip er id on e (12).
To a mixture of freshly ground magnesium turnings (0.457 g,
18.8 mmol) in 20 mL of anhydrous THF at rt was added 1,2-
dibromoethane (0.15 mL, 1.71 mmol). After stirring at rt for
1 h, the MgBr2/THF solution was removed and discarded.
Residual MgBr2 was removed by washing the magnesium with
anhydrous THF. Fresh THF (40 mL) and a portion of
4-(benzyloxy)-1-bromobutane (3.24 mL, 17.1 mmol) were added
to the flask. When the reaction initiated, the flask was cooled
to 0 °C and the remainder of 4-(benzyloxy)-1-bromobutane was
added. The mixture was stirred until most of the magnesium
had reacted. Additional magnesium (0.21 g, 8.5 mmol) was
added, and stirring was continued for 1 h at rt to give the
Grignard reagent.
28.4; IR (NaCl, neat): 3266, 3044, cm-1
C8H13NO2 155.09460 (M+), found 155.09442.
. HRMS calcd for
(+)-(2S)-1-[(Ben zyloxy)ca r bon yl]-2-(3′-h yd r oxyp r op yl)-
2,3-d ih yd r o-4-p yr id on e (9).4a To a stirred solution of 8
(0.992 g, 6.39 mmol) in THF at -78 °C was added n-
butyllithium (2.10 mL, 6.71 mmol, 3.19 M solution in n-
hexane). After stirring at -78 °C for 1 h, benzyl chloroformate
(0.91 mL, 6.39 mmol) was added, and the reaction mixture
was stirred for 1.5 h. Because TLC analysis of the reaction
mixture indicated the presence of starting dihydro-4-pyridone,
an additional portion of benzyl chloroformate (0.30 mL, 2.1
mmol) was added. Stirring was continued for an additional
30 min, 0.2 mL of water was added, and the reaction mixture
was warmed to rt. The crude solution was dried over K2CO3,
filtered, and concentrated to give 2.41 g of the crude product.
Purification by radial PLC (silica gel, EtOAc/hexanes) yielded
1.457 g (79%) of the desired hydroxy 2,3-dihydro-4-pyridone 9
1
as a clear oil: [R]25.5 +103 (c 0.37, CHCl3); H NMR (CDCl3,
D
300 MHz) δ 7.76 (d, 1 H, J ) 7.7 Hz), 7.40 (s, 5 H), 5.18-5.38
(m, 3 H), 4.66 (apparent q, 1 H, J ) 5.9 Hz), 3.60 (apparent t,
2 H, not resolved adequately to obtain J values), 2.83 (dd, 1
H, J ) 6.6 and 16.6 Hz), 2.46 (d, 1 H, J ) 16.7 Hz), 1.35-1.90
(m, 5 H); 13C NMR (CDCl3, MHz) δ 192.9, 152.3, 141.4, 134.7,
128.5 (2 carbons), 128.2, 106.9, 68.8, 61.7, 53.0, 39.5, 28.4, 26.9;
IR (NaCl, neat): 3427, 3089, 3067, 1724, 1663, 1600 cm-1
.
(+)-(2S)-1-[(Ben zyloxy)ca r b on yl]-2-(3′-ch lor op r op yl)-
2,3-d ih yd r o-4-p yr id on e (10). Triphenylphosphine (3.88 g,
14.8 mmol) was added in one portion to a solution of 9 (2.85 g,
9.86 mmol) in 30 mL of anhydrous CH2Cl2 at -42 °C, and the
mixture was stirred until homogeneous. N-Chlorosuccinimide
(1.98 g, 14.8 mmol) was added in one portion, and the mixture
was stirred at -42 °C for 30 min after becoming homogeneous.
After warming to rt, the stirring was continued for 4 h, 0.5
mL of anhydrous methanol was added, and the mixture was
stirred for 20 min. The solvents were removed in vacuo, and
the residue was redissolved in diethyl ether, filtered through
Celite, and concentrated. The crude product was purified by
radial PLC to yield 2.85 g (94%) of the desired dihydropyridone
In a separate flask, copper(I) bromide-dimethyl sulfide
complex (3.51 g, 17.1 mmol) was added to 70 mL of anhydrous
THF and cooled to -78 °C. The Grignard of 4-(benzyloxy)-1-
bromobutane was added slowly via a double-tipped stainless
steel needle. Stirring for 1 h at -78 °C produced an orange
solution that appeared to be almost homogeneous. Boron
trifluoride etherate (2.10 mL, 17.1 mmol) was added, and
stirring was continued for 5 min. To the newly formed BF3‚-
OEt2/organocopper complex was added (over a 1.5 h period) a
solution of 11 (2.75 g, 8.55 mmol) in 35 mL of anhydrous THF.
After stirring for 2 h at -78 °C, 40 mL of aqueous 20% NH4-
Cl/NH4OH (50:50) was added, and the mixture was allowed
to warm to rt. After exposure to air and stirring for several
min, the mixture turns blue. The crude mixture was extracted
with diethyl ether. The organic extracts were washed with
brine and dried over anhydrous K2CO3 for 15 min. Filtration
and concentration in vacuo gave 5.26 g of the crude product
as a dark oil. Purification by radial PLC (silica gel, 10-30%
10 as a clear oil: [R]27.5 +111.6 (c 0.43, CHCl3); 1H NMR
D
(CDCl3, 300 MHz) δ 7.76 (d, 1 H, J ) 7.6 Hz), 7.39 (s, 5 H),
5.15-5.40 (m, 3 H), 4.63 (br s, 1 H), 3.46 (br s, 2 H), 2.84 (dd,
1 H, J ) 6.5 and 16.6 Hz), 2.41 (d, 1 H, J ) 16.5 Hz), 1.55-
1.95 (m, 4 H); 13C NMR (CDCl3, 75 MHz) δ 192.4, 152.4, 141.2,
134.8, 128.8, 128.7, 128.5, 107.3, 69.1, 52.7, 44.1, 40.0, 28.7,
28.1; IR (NaCl, neat): 3089, 3066, 1725, 1670, 1603 cm-1; Anal.
Calcd for C16H18NO3Cl: C, 62.44; H, 5.89; N, 4.55. Found: C,
62.31; H, 5.91; N, 4.55.
EtOAc/hexanes) yielded 3.70 g (89%) of the desired 2,6-cis-
1
piperidone 12 as a clear oil: [R]24.5 -3.0 (c 0.46, CHCl3); H
D
NMR (CDCl3, 300 MHz) δ 7.20-7.45 (m, 10 H), 5.08-5.22
(appears as a doublet at 5.15 ppm with sidebands at 5.20 and
5.11 ppm, 2 H, J ) 2.2 Hz), 4.50 (br s, 1 H), 4.47 (s, 2 H), 4.35
(br s 1 H), 3.48 (br s, 2 H), 3.42 (t, 2 H, J ) 5.2 Hz), 2.81 (dd,
1 H, J ) 9.2 and 15.8 Hz), 2.40 (q, 1 H, J ) 6.6 Hz), 2.31 (dd,
1 H, J ) 4.5 and 15.5 Hz), 1.25-1.90 (series of m, 10 H), 1.18
(+)-(2S,3S)-1-[(Ben zyloxy)car bon yl]-2-(3′-ch lor opr opyl)-
3-m eth yl-2,3-d ih yd r o-4-p yr id on e (11). Lithium bis(trim-
ethylsilyl)amide (10.9 mL, 10.9 mmol, 1.0 M solution in THF)
was added dropwise to a solution of 10 (2.80 g, 9.08 mmol) in
100 mL of THF at -78 °C. After stirring for 1 h at -78 °C,