Organic & Biomolecular Chemistry
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66.9 (CH2, Z), 128.3, 128.3 and 128.7 (CH, Ph, Z), 136.6 (1-C, 28.4 (CH3, Boc), 36.0 (5-C), 42.2 (7-C), 43.8 (3-C), 52.5 (OCH3),
Ph, Z), 156.6 (CO, Z), 169.9 (2-CO), 172.0 (COO). (ESI) m/z = 61.5 (4-C), 79.9 (C, Boc), 155.4 (CO, Boc), 172.8 (COO), 175.6 (2-
335.0 (M + H)+, 357.0 (M + Na)+. Elemental analysis calcd (%) CO). (ESI) m/z = 323.3 (M + Na)+. Elemental analysis calcd (%)
for C17H22N2O5: C 61.07, H 6.63, N 8.38. Found (%): C 61.28, H for C14H24N2O5: C 55.98, H 8.05, N 9.33. Found (%): C 55.73, H
6.55, N 8.18.
8.18, N 9.11.
(3S,4S)-6-Benzyl-1,6-diazaspiro[3.5]nonane-2,5-dione
(13).
(3S,4S)-1-p-Methoxyphenyl-1,6-diazaspiro[3.5]nonane-2,5-
dione (11). To a solution of N-Pmp-2-oxoazetidine 7 (0.242 g,
Syrup (0.051 g, 90%). Eluent: MeOH–CH2Cl2 (1 : 80). [α]D20
=
−45.9 (c 0.4, CHCl3). HPLC tR = 12.50 min (gradient A/B from 0.55 mmol) in MeOH (100 mL), 10 wt% Pd/C was added
5 : 95 to 50 : 50 over 20 min). 1H-NMR (300 MHz, CDCl3): δ 1.29 (0.058 g, 0.06 mmol), and the suspension was hydrogenated at
(d, 3H, J = 7.5, 3-CH3), 1.79 (m, 1H, 8-H), 1.95 (m, 1H, 8-H), rt and atmospheric pressure for 6 h. After filtration of the cata-
2.08 (m, 1H, 9-H), 2.15 (m, 1H, 9-H), 3.06 (q, 1H, J = 7.5, 3-H), lyst, the solvent was evaporated and the crude mixture was pur-
3.26 (m, 2H, 7-H), 4.28 (d, 1H, J = 14.5, 6-CH2), 4.96 (d, 1H, J = ified by flash chromatography using MeOH–CH2Cl2 (1 : 50) as
14.5, 6-CH2), 6.13 (s, 1H, 1-H), 7.29 (m, 5H, CH, Bn). 13C-NMR eluent, affording 11 (0.127 g, 84%) as a solid. mp 105–108 °C,
(75 MHz, CDCl3): δ 10.9 (3-CH3), 21.0 (8-C), 33.9 (9-C), 47.2 (7- CH2Cl2. [α]2D0 = −60.9 (c 0.8, CHCl3). HPLC tR = 11.02 min (gra-
C), 50.7 (6-CH2), 57.7 (3-C), 60.2 (4-C), 127.8, 128.5, 128.8 and dient A/B from 5 : 95 to 50 : 50 over 20 min). 1H-NMR
136.9 (1-C and CH, Bn), 169.4 and 170.3 (CO). (ESI) m/z = 259.1 (300 MHz, CDCl3): δ 1.36 (d, 3H, J = 7.4, 3-CH3), 1.88 (m, 1H,
(M + H)+, 539.3 (2M + Na)+. Elemental analysis calcd (%) for 8-H), 2.00 (m, 1H, 9-H), 2.08 (m, 1H, 8-H), 2.51 (td, 1H, J = 14.1
C15H18N2O2: C 69.74, H 7.02, N 10.84. Found (%): C 69.60, H and 3.9, 9-H), 3.14 (q, 1H, J = 7.4, 3-H), 3.41 (m, 2H, 7-H), 3.76
7.18, N 10.71.
(3S,4S)-4-[3′-(Benzyloxycarbonyl)amino]propyl-1-tert-butoxy- and 5-H, Pmp), 7.28 (d, 2H, J = 9.0, 2-H and 6-H, Pmp).
carbonyl-4-methoxycarbonyl-3-methyl-2-oxoazetidine
(9). A 13C-NMR (75 MHz, CDCl3): δ 10.1 (3-CH3), 21.0 (8-C), 30.9 (9-
(s, 3H, p-OCH3), 6.50 (bs, 1H, 6-NH), 6.84 (d, 2H, J = 9.0, 3-H
solution of the 1-NH oxoazetidine 8 (0.050 g, 0.15 mmol) in C), 42.6 (7-C), 55.6 (p-OCH3), 57.1 (3-C), 64.3 (4-C), 114.5 (3-CH
dry CH2Cl2 (4 mL) was successively treated with TEA and 5-CH, Pmp), 120.1 (2-CH and 6-CH, Pmp), 130.0 (1-C,
(0.021 mL, 0.15 mmol), DMAP (0.002 g, 0.015 mmol) and di- Pmp), 156.5 (4-C, Pmp), 166.3 and 169.3 (CO). (ESI) m/z = 275.1
tert-butyldicarbonate (0.033 g, 0.15 mmol), and stirred for 3 h. (M + H)+, 297.1 (M + Na)+. Elemental analysis calcd (%) for
Then, the solvent was evaporated to dryness and the residue C15H18N2O3: C 65.68, H 6.61, N 10.21. Found (%): C 65.60, H
was purified on a silica gel column using EtOAc–hexane (1 : 1) 6.54, N 10.32.
as eluent, yielding 9 (0.061 g, 94%) as a syrup. [α]2D0 = −19.4
(3S,4S)-6-Benzyl-1-p-methoxyphenyl-1,6-diaza-spiro[3.5]-
(c 1.3, CHCl3). HPLC tR = 15.59 min (gradient A/B from 5 : 95 to nonane-2,5-dione (12). A solution of the spiro-β-lactam 11
1
80 : 20 over 20 min). H-NMR (300 MHz, CDCl3): δ 1.16 (d, 3H, (0.096 g, 0.35 mmol) in dry CH3CN (4 mL) was treated with
J = 7.5, 3-CH3), 1.49 (s, 9H, CH3, Boc), 1.55 (m, 1H, 2′-H), 1.78 BTPP (0.214 mL, 0.70 mmol) and BnBr (0.084 mL, 0.70 mmol).
(m, 1H, 2′-H), 2.14 (m, 2H, 1′-H), 3.21 (q partially overlapped, After microwave heating at 120 °C for 1 h, the solvent was
1H, J = 7.5, 3-H), 3.23 (m, 2H, 3′-H), 3.78 (s, 3H, OCH3), 4.85 (s, evaporated to dryness and the residue was dissolved in EtOAc
1H, 3′-NH), 5.09 (s, 2H, CH2, Z), 7.35 (s, 5H, CH, Ph, Z). and washed with H2O and brine. The organic layer was dried
13C-NMR (75 MHz, CDCl3): δ 9.4 (3-CH3), 24.6 (2′-C), 28.1 (CH3, over Na2SO4 and evaporated to dryness. The crude mixture was
Boc), 30.4 (1′-C), 41.0 (3′-C), 52.3 (3-C), 52.6 (OCH3), 66.6 (4-C), purified by chromatography on silica gel using MeOH–CH2Cl2
66.9 (CH2, Z), 83.9 (C, Boc), 128.3, 128.3 and 128.7 (CH, Ph, Z), (1 : 80) as eluent, yielding 12 (0.125 g, 98%) as a syrup. [α]D20
=
136.6 (1-C, Ph, Z), 147.6 (CO, Boc), 156.5 (CO, Z), 166.5 (2-CO), −50.0 (c 0.5, CHCl3). HPLC tR = 15.57 min (gradient A/B from
170.3 (COO). (ESI) m/z = 457.2 (M + Na)+. Elemental analysis 20 : 80 to 60 : 40 over 20 min). 1H-NMR (300 MHz, CDCl3):
calcd (%) for C22H30N2O7: C 60.82, H 6.96, N 6.45. Found (%): δ 1.37 (d, 3H, J = 7.4, 3-CH3), 1.89 (m, 1H, 8-H), 2.00 (m, 1H,
C 60.72, H 6.77, N 6.32.
(3S,4S)-4-(tert-Butoxycarbonyl)amino-4-methoxy-carbonyl-3- (q, 1H, J = 7.4, 3-H), 3.35 (m, 2H, 7-H), 3.78 (s, 3H, p-OCH3),
methyl-2-oxoazepane (10). A solution of (0.048 g, 4.51 (d, 1H, J = 14.3, 6-CH2), 4.84 (d, 1H, J = 14.3, 6-CH2), 6.83
9-H), 2.04 (m, 1H, 8-H), 2.51 (td, 1H, J = 13.0 and 3.9, 9-H), 3.13
9
0.11 mmol) in MeOH (10 mL) was treated with 10 wt% Pd/C (d, 2H, J = 9.1, 3-H and 5-H, Pmp), 7.24 (d, 2H, J = 9.1, 2-H and
(0.011 g, 0.01 mmol). The suspension was hydrogenated at rt 6-H, Pmp), 7.33 (m, 5H, CH, Bn). 13C-NMR (75 MHz, CDCl3):
and atmospheric pressure for 2 h. After filtration of the cata- δ 10.4 (3-CH3), 20.7 (8-C), 31.3 (9-C), 47.3 (7-C), 50.9 (6-CH2),
lyst, the solvent was evaporated and the crude mixture was 55.7 (p-OCH3), 57.2 (3-C), 64.7 (4-C), 114.5 (3-CH and 5-CH,
purified by column chromatography using EtOAc–hexane Pmp), 120.2 (2-CH and 6-CH, Pmp), 127.9, 128.8 and 128.9
(3 : 2) as eluent, yielding 10 (0.030 g, 90%) as a white solid. mp (CH, Bn), 130.2 (1-C, Pmp), 137.1 (1-C, Bn), 156.4 (4-C, Pmp),
183–186 °C, CH2Cl2. [α]2D0 = −40.2 (c 0.7, CHCl3). HPLC tR
=
166.4 and 167.0 (CO). (ESI) m/z = 365.1 (M + H)+, 387.1 (M +
11.02 min (gradient A/B from 5 : 95 to 50 : 50 over 20 min)). Na)+. Elemental analysis calcd (%) for C22H24N2O3: C 72.50, H
1H-NMR (300 MHz, CDCl3): δ 1.05 (d, 3H, J = 7.0, 3-CH3), 1.42 6.64, N 7.69. Found (%): C 72.58, H 6.70, N 7.48.
(s, 9H, CH3, Boc), 1.74 (m, 2H, 6-H), 2.19 (m, 1H, 5-H), 3.07
Methyl
(2S,3S)-3-tert-butoxycarbonylamino-2-methyl-3-
(m, 1H, 5-H), 3.12 (q, 1H, J = 7.0, 3-H), 3.23 (m, 1H, 7-H), 3.37 (1′-benzyl-2′-oxopiperidin-3′-yl)propionate (14). A solution of
(m, 1H, 7-H), 3.74 (s, 3H, OCH3), 4.88 (s, 1H, 4-NH), 6.07 (s, compound 13 (0.030 g, 0.12 mmol) in dry CH2Cl2 (5 mL) was
1H, 1-H). 13C-NMR (75 MHz, CDCl3): δ 13.0 (3-CH3), 25.0 (6-C), treated with triethylamine (0.016 mL, 0.116 mmol), DMAP
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Org. Biomol. Chem., 2015, 13, 5195–5201 | 5199