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10
tert
-Butyl
N
-Allyl-
N
-(3-oxopropyl)carbamate (6)
Acrolein
(16.9 g, 302 mmol) and camphorsulfonic acid (1.40 g, 6.04 mmol)
were added to an ice-cooled solution of N-Boc allylamine
(5, 4.75 g, 30.2 mmol) in CH2Cl2 (75
mL). The resulting solution was stirred at 0 ˚C
for 15 min and at 23 ˚C for 30 min. The mixture
was then washed with sat. NaHCO3 solution (75 mL), and
the organic layer was dried (MgSO4). After filtration,
the solvent was removed, and the residue was purified by chromatography
on SiO2 (hexane-MTBE, 1:1; R
f
= 0.33)
to yield the title compound 6 (4.34 g,
20.4 mmol, 67%) as a colorless liquid. ¹H
NMR (500 MHz, CDCl3): δ = 1.42
(s, 9 H), 2.61-2.69 (m, 2 H), 3.45-3.53 (m, 2
H), 3.76-3.85 (m, 2 H), 5.05-5.15 (m, 2 H), 5.67-5.80
(m, 1 H), 9.76 (t, J = 1.6
Hz, 1 H) ppm. ¹³C{¹H} NMR
(125 MHz, CDCl3): δ = 28.29
(3 × CH3), 40.64 (CH2),
43.34 (CH2), 50.42 (CH2), 79.97 (C), 116.36
(CH2), 133.95 (CH), 155.16 (C), 200.85 (CH) ppm. IR (ATR):
3084 (w), 2976 (w), 2932 (w), 2725 (w), 1723 (m), 1687 (vs), 1463
(m), 1407 (s), 1366 (s), 1247 (s), 1168 (vs), 1145 (vs), 920 (m), 864
(m), 774 (m) cm-¹. MS (CI, isobutane): m/z (%) = 214 (49) [M + H+],
158 (100). HRMS: m/z calcd for
C11H20NO3: 214.1443; found: 214.1437 [M + H+];
C11H19NO3 (213.27).
11
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Jencks WP.
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Huie EM.
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Keller K.
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1970,
1117
14
tert
-Butyl 7-Benzyl-8-oxa-3,7-diazabicyclo[4.2.1]nonane-3-carboxylate
(9)
Benzylhydroxylamine (485 mg, 3.94 mmol) was added
to a solution of aldehyde 6 (800 mg, 3.75
mmol) in MeCN (16 mL), and the mixture was stirred for 30 min at
23 ˚C and for 16 h under reflux. The solvent was
evaporated, and the residue was chromatographed on SiO2 (hexane-EtOAc,
2:1; R
f
= 0.29)
to yield the title compound 9 (964 mg,
3.03 mmol, 81%) as a colorless solid, mp 65-66 ˚C.
Due to the carbamate group, NMR spectra show a partially doubled signal
set. ¹H NMR (500 MHz, CDCl3): δ = 1.47
(s, 9 H), 1.55-1.70 (m, 2 H, 5-H), 1.83-1.89 (m,
1 H, 9-H), 2.49-2.57 (m, 1 H, 9-H), 2.94 (d, J = 14.6 Hz,
1/2 H, 2-H), 3.04 (d, J = 14.7
Hz, 1/2 H, 2-H), 3.08-3.15 (m, 1/2 H,
4-H), 3.15-3.23 (m, 1/2 H, 4-H), 3.43-3.47
(m, 1 H, 6-H), 3.73 (d, J = 12.8
Hz, 1/2 H, BnCH2), 3.75 (d, J = 12.6
Hz, 1/2 H, BnCH2), 3.77-3.83 (m, 1/2
H, 4-H), 3.83-3.86 (m, 1/2 H, 2-H), 3.94-3.99
(m, 1/2 H, 4-H), 4.01-4.07 (m, 1/2 H,
2-H), 4.06 (d, J = 12.7
Hz, 1 H, BnCH2), 4.69 (dd, J = 8.8,
3.4 Hz, 1/2 H, 1-H), 4.72 (dd, J = 8.7,
3.6 Hz, 1/2 H, 1-H), 7.25-7.30 (m, 1 H), 7.31-7.39
(m, 4 H) ppm. ¹³C{¹H} NMR
(125 MHz, CDCl3): δ = 28.27
(3 × CH3), 32.10 (1/2
CH2, C-9), 32.23 (1/2 CH2, C-9),
32.95 (1/2 CH2, C-5), 33.57 (1/2 CH2,
C-5), 42.00 (1/2 CH2, C-4), 42.58 (1/2
CH2, C-4), 49.72 (1/2 CH2, C-2),
50.79 (1/2 CH2, C-2), 60.35 (1/2 CH,
C-6), 60.48 (1/2 CH, C-6), 62.77 (CH2, Ph-CH2),
77.52 (1/2 CH, C-1), 77.70 (1/2 CH, C-1), 79.24
(1/2 C, BocC), 79.41 (1/2 C, BocC), 127.24 (CH),
128.27 (2 × CH), 128.80 (CH), 128.86
(CH), 137.37 (C), 154.87 (1/2 C), 155.48 (1/2
C) ppm. IR (ATR): 2975 (m), 2952 (m), 2910 (m), 1688 (vs), 1461
(s), 1413 (vs), 1364 (s), 1322 (s), 1172 (vs), 1125 (vs), 1063 (s),
984 (s), 878 (vs), 810 (m), 744 (vs), 698 (s) cm-¹.
MS (CI, isobutane): m/z (%) = 319
(100) [M + H+], 263
(16). HRMS: m/z calcd for C18H27N2O3:
319.2022; found: 319.2015 [M + H+];
C18H26N2O3 (318.41).
15
cis
-5-(Benzyloxycarbonylamino)-1-(
tert
-butyloxy-carbonyl)-3-hydroxyazepane
(10)
Pd/C (100 mg, 10% w/w
Pd) and ammonium formate (315 mg, 5.00 mmol) were added to a solution
of isoxazolidine 9 (318 mg, 1.00 mmol)
in MeOH (8 mL), and the mixture was heated under reflux for 3 h.
After cooling, the mixture was filtered through Celite, the residue
was rinsed with CH2Cl2 (ca. 15 mL), and the
filtrate was evaporated. The residue was dissolved in MeOH (3 mL)
and the solution cooled in an ice bath. CbzCl (239 mg, 1.40 mmol)
and Et3N (142 mg, 1.40 mmol) were added, the ice bath
was removed, and the mixture stirred at 23 ˚C
for 16 h. After removing the solvents under reduced pressure the
residue was purified by chromatography on SiO2 (hexane-MTBE,
10: 1; R
f
= 0.27) to
give the title compound 10 (240 mg, 0.659
mmol, 66%) as a colorless resin. Due to the carbamate group,
NMR spectra show a partially doubled signal set, ratio ca. 2:1. ¹H
NMR (500 MHz, CDCl3): δ = 1.42
(s, 18/3 H), 1.46 (s, 9/3 H), 1.74-1.85
(m, 2 H), 1.87-1.96 (m, 1 H), 2.01-2.10 (m, 1
H), 3.14 (dt, J = 14.1,
5.6 Hz, 1 H), 3.23 (dd, J = 15.0,
2.7 Hz, 1 H), 3.28-3.41 (m, 1 H), 3.49-3.61 (m,
2/3 H), 3.64-3.71 (m, 2/3 H), 3.74-3.80
(m, 1/3 H), 3.84 (dd, J = 14.9,
4.6 Hz, 2/3 H), 3.88-3.94 (m, 2/3 H),
4.02-4.09 (m, 1/3 H), 4.11-4.17 (m, 2/3
H), 5.08 (s, 2 H), 5.55 (d, J = 7.2
Hz, 1/3 H), 5.88 (d, J = 6.7
Hz, 2/3 H), 7.28-7.33 (m, 1 H), 7.33-7.37
(m, 4 H) ppm. ¹³C{¹H} NMR
(125 MHz, CDCl3): δ = 28.17
(6/3 CH3), 28.31 (3/3 CH3),
32.37 (1/2 CH2), 33.62 (1/2 CH2), 40.26
(1/2 CH2), 41.76 (1/2 CH2),
43.64 (1/2 CH2), 43.93 (1/2 CH2),
47.90 (CH), 50.17 (1/2 CH2), 52.63 (1/2
CH2), 66.36 (1/2 CH2), 66.68 (1/2
CH2), 68.78 (1/2 CH), 69.96 (1/2 CH), 80.11
(1/2 C), 80.32 (1/2 C), 127.93 (2 CH), 128.02
(CH), 128.34 (2 ¥ CH), 136.45 (C), 154.98
(1/2 C), 155.53 (1/2 C), 157.49 (C) ppm. IR (ATR):
3324 (m), 3065 (w), 3034 (w), 2975 (m), 2930 (m), 1689 (vs), 1668
(vs),1527 (m), 1479 (m), 1454 (m), 1416 (s), 1366 (s), 1248 (s),
1160 (vs),
1058 (s), 1027 (s), 865 (m), 736 (s), 697 (s)
cm-¹. MS (CI, isobutane): m/z (%) = 365 (28) [M + H+],
309 (100). HRMS: m/z calcd for
C19H29N2O5: 365.2077;
found: 365.2068 [M + H+];
C19H28N2O5 (364.44).
16
cis
-3-Acetoxy-5-(benzyloxycarbonylamino)-1-(
tert
-butyl-oxycarbonyl)azepane
(12)
Pyridine (316 mg, 3.99 mmol) and Ac2O
(407 mg, 3.99 mmol) were added to a solution of azepanol 10 (969 mg, 2.66 mmol) in CH2Cl2 (10
mL). The solution was stirred at 23 ˚C for 24
h, and then the solvent was removed in vacuum. The residue was chromatographed
on SiO2 (hexane-MTBE, 1:2; R
f
= 0.26)
to yield ester 12 as a colorless oil (960
mg, 2.36 mmol, 89%). Due to the carbamate groups NMR spectra
show a partially doubled signal set. ¹H NMR
(500 MHz, CDCl3): δ = 1.45
(s, 1/2 × 9 H), 1.47 (s, 1/2 × 9
H), 1.74-1.94 (m, 2 H), 1.96-2.01 (m, 1 H), 2.02
(s, 1/2 × 3 H), 2.05 (s, 1/2 × 3
H), 2.07-2.12 (m, 1 H), 3.14-3.26 (m, 1 H), 3.38-3.46
(m, 1/2 H), 3.50-3.66 (m, 2 H), 3.72-3.85
(m, 1 H), 3.88-3.96 (m, 1/2 H), 5.00-5.15
(m, 7/2 H), 5.22 (d, J = 7.4
Hz, 1/2 H), 7.30-7.39 (m, 5 H) ppm. ¹³C{¹H} NMR (125
MHz, CDCl3): δ = 21.06
(CH3), 28.23 (3 CH3), 33.25 (1/2
CH2), 33.94 (1/2 CH2), 38.28 (1/2
CH2), 38.77 (1/2 CH2), 43.58 (1/2
CH2), 44.12 (1/2 CH2), 47.62 (1/2
CH), 47.93 (1/2 CH), 49.94 (CH2), 66.51 (CH2),
70.51 (CH), 79.81 (1/2 C), 79.98 (1/2 C), 127.97
(2 CH), 128.02 (CH), 128.40 (2 CH), 136.35 (C), 155.04 (C), 155.27
(C), 169.67 (C) ppm. IR (ATR): 3327 (w), 2975 (w), 2936 (w), 1690 (vs),
1525 (m), 1455 (m), 1415 (m), 1366 (m), 1231 (vs), 1157 (s), 1030
(s), 699 (m), 646 (m), 624 (m) cm-¹.
MS (CI, isobutane): m/z (%) = 407 (16) [M + H+],
351 (100), 307 (17). HRMS: m/z calcd
for C21H31N2O6: 407.2182;
found: 407.2180 [M + H+];
C21H30N2O6 (406.47).
