M. Hirama et al. / Tetrahedron 66 (2010) 7618e7624
7623
C20H28N2O5S (Mþ) 408.1719, found 408.1703. Anal. Calcd for: C,
63.81; H, 6.43; N, 5.95. Found: C, 63.61; H, 6.71; N, 5.78.
camphorsultam 2, which was crystallized from hexane as a white
crystalline solid.
4.2.4.4. (1R,4S,7R)-7-((10R)-2,10-Camphorsultam-40-carbonyl)-2-
aza-bicyclo[2.2.2]oct-5-ene-2-carboxylic acid methyl ester (1R)-5a. The
de of endo-(1R)-5a was determined by HPLC analysis using a TOSOH
TSK-GEL Silica-60; 1% EtOH/hexane; flow rate, 1.0 ml/min: re-
tention time, major (1R)-5a 60 min, minor (1S)-5a 63 min. White
4.2.6.1. N-Acryloyl (1S)-2,10-camphorsultam 2. White solid
(recrystallized from hexane), 84% yield, mp: 192e195 ꢁC; lit.12a mp:
23
23
191e193 ꢁC. [
a
]
ꢀ102 (c 1.0, CHCl3); lit.6c
[a
]
ꢀ100.9 (c 0.983,
D
D
CHCl3). 1H NMR [ppm] (270 MHz, CDCl3, 25 ꢁC):
d
0.98 (3H, s), 1.18
(3H, s),1.47e1.33 (2H, m),1.99e1.89 (3H, m), 2.14e2.06 (2H, m), 3.49
(2H, q, J¼21.6, 13.8 Hz), 3.94 (1H, t, J¼6.4 Hz), 5.86 (1H, dd, J¼10.9,
1.5 Hz), 6.50 (1H, dd, J¼16.7, 1.5 Hz), 6.87 (1H, dd, J¼16.7, 10.4 Hz);
solid, mp: 203e204 ꢁC. 1H NMR (CDCl3, 270 MHz, 25 ꢁC):
d 0.97 (3H,
s) 1.21 (3H, s), 1.30e1.45 (2H, m), 1.84e2.06 (7H, m), 2.86e2.94 (2H,
m), 3.24e3.28 (1H, m), 3.38e3.54 (2H, m), 3.67e3.75 (4H, m), 3.82
(1H, br s), 5.03e5.17 (1H, m), 6.18e6.29 (1H, m), 6.44e6.50 (1H, m);
13C NMR [ppm] (67.8 MHz, CDCl3, 25 ꢁC):
d 19.86, 20.85, 26.47, 32.86,
38.40, 44.67, 47.80, 48.56, 53.10, 65.11, 127.74, 131.39, 163.82.
13C NMR (CDCl3, 67.8 MHz, 25 ꢁC):
d 19.77 (CH3), 20.65 (CH3), 25.82,
26.42, 30.82, 32.60, 38.30, 44.35, 45.10, 46.50, 46.95, 47.76, 48.39,
4.2.6.2. N-Acryloyl (1R)-2,10-camphorsultam 2. White solid
23
52.31, 52.81, 65.08, 129.76, 134.77, 155.43, 171.49. IR (NaCl) 3020,
(recrystallized from h23exane), 74% yield, mp: 196e198 ꢁC. [
a]
D
23
23
2962, 1215, 1691, 1454, 1398, 1338 cmꢀ1. [
(99% de).
a
]
þ39.8 (c 1.0, CHCl3)
þ104 (c 1.0, CHCl3) lit.9
[
a
]
þ102 (c 1.7, CHCl3). 1H NMR [ppm]
D
D
(270 MHz, CDCl3, 25 ꢁC):
d 0.98 (3H, s), 1.18 (3H, s), 1.47e1.33 (2H,
m), 1.99e1.89 (3H, m), 2.14e2.06 (2H, m), 3.49 (2H, q, J¼21.6,
13.8 Hz), 3.94 (1H, t, J¼6.4 Hz), 5.86 (1H, dd, J¼10.9, 1.5 Hz), 6.50
(1H, dd, J¼16.7, 1.5 Hz), 6.87 (1H, dd, J¼16.7, 10.4 Hz); 13C NMR
4.2.5. Ester exchange reaction of 5a. The solution of 10% LiO-
MeeMeOH (570 mg, 1.5 mmol) in MeOH (5 mL) was cooled at 0 ꢁC.
To the solution was added the solution of endo (1S)-5a (204 mg,
0.5 mmol) in THF (2 mL), and the mixture was stirred at 0 ꢁC for 4 h.
The reaction was quenched by addition of saturated ammonium
chloride, and the product was extracted with chloroform. The or-
ganic solution was dried over sodium sulfate and filtered. After
removal of solvent, the residue was purified by column chroma-
tography on silica gel (10% MeOH in chloroform) to give product
(1S,4R,7S)-6 as colorless oil.
[ppm] (67.8 MHz, CDCl3, 25 ꢁC):
d 19.86, 20.85, 26.47, 32.86, 38.40,
44.67, 47.80, 48.56, 53.10, 65.11, 127.74, 131.39, 163.82.
4.2.7. Preparation of 1-phenoxycarbonyl-1,2-dihydropyridine 18. Py-
ridine (24.0 g, 303 mmol) and NaBH4 (6.0 g, 159 mmol) were stirred
together at ꢀ78 ꢁC in ethanol (180 mL), and then phenyl chlor-
oformate (32.0 g, 204 mmol) was added slowly to the solution by
a dropping funnel for 1 h. The mixture was stirred at ꢀ78 ꢁC for
24 h. The solution was poured into ice-water, and the mixture was
stirred until the H2 bubble stopped. The mixture was extracted with
diethyl ether (100 mLꢂ3) and the ether solution was dried over
sodium sulfate. The organic layer was filtered and the diethyl ether
removed in vacuo. The residue was recrystallized from ethanol to
give the product 1 as a white solid in 67% yield (27.50 g,
136.7 mmol). The ratio of 1,2-dihydropyridine and 1,4-dihy-
dropyridine was 93 to 7. Mp: 64e66 ꢁC. 1H NMR [ppm] (270 MHz,
4.2.5.1. (1S,4R,7S)-2-Methoxycarbonyl-2-azabicyclo[2.2.2]oct-5-
ene-7-methyl carboxylate (7S)-6. Ester exchange reaction was car-
ried out to give (7S)-6 as colorless oil in 54% yield. 1H NMR (CDCl3,
270 MHz, 25 ꢁC):
d 1.85e1.87 (2H, m), 2.83 (1H, br s), 2.90e2.98
(1H, m) 3.06e3.12 (1H, m), 3.24e3.39 (1H, m), 3.64e3.72 (6H, m),
4.90e5.17 (1H, m), 6.28e6.48 (2H, m); 13C NMR (CDCl3, 67.8 MHz,
25 ꢁC):
135.00, 155.83, 173.10. [
CHCl3).
d 25.85, 30.46, 43.58, 46.89, 47.19, 51.85, 52.40, 130.45,
a]
23 þ116 (c 0.6, CHCl3); lit.11
[
a
]
D
23 þ109 (c 1,
CDCl3, 25 ꢁC):
d
4.45 (1H, q, J¼3.8, 2.0 Hz), 4.59 (1H, br s), 5.31e5.22
D
(1H, m), 5.62e5.59 (1H, m), 5.93e5.88 (1H, m), 6.84 (1H, dd, J¼20.0,
7.7 Hz), 7.13 (2H, d, J¼7.6), 7.22 (1H, t, J¼8.2 Hz), 7.38 (2H, t,
4.2.5.2. (1R,4S,7R)-2-Methoxycarbonyl-2-azabicyclo[2.2.2]oct-5-
ene-7-methyl carboxylate (7R)-6. Ester exchange reaction of (1R)-
5a was carried out to give (7R)-6 as colorless oil in 49% yield. 1H
J¼7.8 Hz); 13C NMR (CDCl3, 67.8 MHz, 25 ꢁC):
d 43.78, 105.82, 119.47,
121.54 (2C), 121.82, 125.35, 125.67, 126.06, 129.36 (2C), 150.81.
NMR (CDCl3, 270 MHz, 25 ꢁC):
d
1.85e1.87 (2H, m), 2.83 (1H, br s),
4.2.8. Preparation of 1-methoxycarbonyl-1,2-dihydropyridine 48. Py-
ridine (4.74 g, 60 mmol) and NaBH4 (2.60 g, 68 mmol) were stirred
in ethanol (50 mL) at ꢀ78 ꢁC, and then methyl chloroformate
(5.68 g, 60 mmol) was added slowly to the solution by a dropping
funnel for 1 h. The mixture was stirred at ꢀ78 ꢁC for 24 h. The so-
lution was poured into ice-water, and the mixture was stirred until
the H2 bubble stopped. The mixture was extracted with diethyl
ether (100 mLꢂ3) and the ether solution was dried over sodium
sulfate. The organic layer was filtered and the diethyl ether re-
moved in vacuo. The product was purified by column chromatog-
raphy on silica gel (10% ethyl acetate in hexane) to give the product
1 as a colorless oil in 98% (8.18 g, 58.8 mmol). The ratio of 1,2-
dihydropyridine and 1,4-dihydropyridine was 94 to 6. 1H NMR
2.90e2.98 (1H, m) 3.06e3.12 (1H, m), 3.24e3.39 (1H, m), 3.64e3.72
(6H, m), 4.90e5.17 (1H, m), 6.28e6.48 (2H, m); 13C NMR (CDCl3,
67.8 MHz, 25 ꢁC):
130.45, 135.00, 155.83, 173.10. [
ꢀ110 (c 1, CHCl3).
d 25.85, 30.46, 43.58, 46.89, 47.19, 51.85, 52.40,
23
23
a
]
ꢀ98 (c 0.6, CHCl3); lit.11
[a]
D
D
4.2.6. Preparation of N-acryloyl 2,10-camphorsultam 26c,9. To the
solution of acrylic acid (1.3 equiv) and triethylamine (2.5 equiv) in
THF (volume corresponded to 0.2 M of 2,10-camphorsultam) was
added acryloyl chloride (1.2 equiv) at ꢀ20 ꢁC. A white solid was
formed instantaneously. The mixture was stirred at ꢀ20 ꢁC for 1 h.
Lithium chloride (1.1 equiv) was added, followed by 2,10-cam-
phorsultam (5.0 g, 23.2 mmol). The mixture was allowed to warm
to room temperature and stirred for 48 h. The reaction was
quenched by addition of 0.2 M HCl (2 equiv), and THF was removed
in vacuo. The residue was partitioned between ethyl acetate and
0.2 M HCl (0.5 equiv). The organic layer was washed subsequently
with 0.2 M HCl, brine, 1 M sodium bicarbonate (two times), and
brine. The organic solution was then dried over sodium sulfate and
filtered. Ethyl acetate was removed in vacuo, and the residue was
dissolved in toluene. The toluene solution was filtered through
a silica gel bed, and the cake was washed with toluene. Concen-
tration of toluene solution to dryness afforded the N-acryloyl 2,10-
[ppm] (270 MHz, CDCl3, 25 ꢁC):
d 3.78 (3H, s), 4.27e4.16(1H, m),
4.36 (1H, br s), 5.14e5.12 (1H, m), 5.52e5.51 (1H, m), 5.86e5.81
13
(1H, m), 6.66e6.63 (1H, m); C NMR (CDCl3, 67.8 MHz, 25 ꢁC)
d
43.35, 52.91, 104.61, 118.91, 121.73, 125.41, 149.57.
4.2.9. Preparation of N-3-chloropropanoyl (1S)-2,10-camphor sul-
tam12. To a suspension of NaH (38.5 mg, 1.6 mmol) and toluene
(5 mL) was added (1S)-2,10-camphorsultam (215 mg, 1 mmol). Af-
ter 1 h at room temperature, CuCl (13 mg, 0.13 mmol) was added.
The mixture was added to a solution of 3-chloropropionyl chloride
in toluene (2 mL). After 30 min, the reaction mixture was quenched