Building Block for Cyclopropyl-Containing Amino Acids
Methyl 2-(Benzyloxycarbonylamido)-5-oxo-tetrahydrofuran-2-car-
boxylate (11): To a solution of 2 (150 mg, 0.57 mmol) in CH2Cl2
(10 mL) was added at 0 °C 75% mCPBA (262 mg, 1.14 mmol). The
mixture was stirred at room temp. for 2 h, and the solvent was
removed under reduced pressure. The title compound (70 mg, 42%)
was isolated by column chromatography on silica gel (hexane/ethyl
acetate, 1:1, Rf = 0.24) as a colorless solid, m.p. 138 °C [lit.[20] 136
–138 °C] 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.35 (s, 5 H, Ph),
(+, 2 CH, Ph), 128.0 (+, CH, Ph), 127.9 (+, CH, Ph), 127.8 (+, 2
CH, Ph), 82.0 (–, 2 Cquat, tBu), 80.7 (–, CH2), 80.5 (–, CH2), 66.1
(–, CH2), 65.9 (–, CH2), 65.7 (–, CH2), 64.8 (–, CH2), 59.5 (+, CH),
57.1 (+, CH), 52.3 (+, 2 C, CO2CH3), 51.4 (–, CH2), 51.3 (–, CH2),
41.8 (–, Cquat, cPr), 41.4 (–, Cquat, cPr), 27.5 (+, CH3, tBu), 17.4
(–, CH2, cPr), 15.0 (–, CH2, cPr), 11.5 (–, CH2, cPr), 10.2 (–, CH2,
cPr) ppm. MS (ESI): m/z (%) = 1048.8 (58) [2M + Na]+, 535.0
(100) [M + Na]+. IR (film): ν = 3323 (NH), 2977, 2923, 1726
˜
6.56 (s, 1 H, NH), 5.12 (d, J = 3.1 Hz, 2 H, CH2Ph), 3.85 (s, 3 H, (C=O), 1670 (C=O), 1454, 1407, 1369, 1347, 1233, 1154, 843, 748,
CO2CH3), 3.07–2.90 (m, 1 H), 2.84–2.58 (m, 3 H) ppm. 13C NMR 701 cm–1. C22H29BrN2O7 (513.38): calcd. C 51.47, H 5.69, N 5.46;
(125.7 MHz, CDCl3, APT, 25 °C): δ = 174.8 (–, Cquat, CO2Me), found C 51.71, H 5.52, N 5.75.
168.3 (–, Cquat, CO2Me), 153.7 (–, Cquat, NHCO2), 135.2 (–,Cquat
,
Methyl 4-(tert-Butoxycarbonylmethyl)-5-oxo-7-(benzyloxycarbonyl)-
4,7-diazapiro[2.5]octane-8-carboxylate (14): To a solution of 13
(1.90 g, 3.70 mmol) in THF (50 mL) was added nBu4NI (2.05 g,
5.55 mmol) and Cs2CO3 (1.81 g, 5.55 mmol). The resulting suspen-
sion was stirred at 20 °C for 5 h, then the solvent was removed at
reduced pressure. The residue was purified by column chromatog-
raphy on silica gel (hexane/ethyl acetate, 1:1, Rf = 0.11) to afford
1.44 g (90%) of 14 as a colorless oil. The NMR spectra recorded
at ambient temperature indicated two rotamers A:B in a ratio of
Cipso), 128.5 (+, 2 C, Ph-CH), 128.4 (+, Ph-CH), 128.2 (+, 2 C, Ph-
CH), 89.2 (–, CH2), 67.5 (–, CH2Ph), 54.1 (+, CO2CH3), 30.0 (–,
Cquat), 28.5 (–, CH2) ppm. MS (ESI): m/z (%) = 609.2 (80) [2M +
Na]+, 316.0 (100) [M + Na]+. IR (film): ν = 3296 , 3061, 2954,
˜
1798, 1781, 1703, 1544, 1355, 1311, 1202, 1052, 1009, 952, 754, 627
cm–1. C14H15NO6 (293.27): calcd. C 57.34, H 5.16, N 4.78; found
C 57.34, H 5.16, N 4.78.
Methyl 2-(Benzyloxycarbonylamino)-2-[1-(tert-butoxycarbonylmeth-
1
ylamino)cyclopropyl]acetate (12): To
a
solution of
2
(2.56 g,
2:1. H NMR (300 MHz, CDCl3): δ = 7.38–7.25 (m, 5 H, Ph, A,
9.78 mmol) and glycine tert-butyl ester (1.18 g, 10.3 mmol) in ace-
tonitrile (100 mL) was added K2CO3 (1.49 g, 10.8 mmol). The re-
sulting suspension was stirred at room temperature for 3 d, then
the solvent was removed at reduced pressure and the residue was
purified by column chromatography (hexane/diethyl ether, 2:1 Rf =
0.13) to give 3.19 g (83%) of 12 as a colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 7.38–7.31 (m, 5 H, Ph), 5.97 (d, J = 8.3 Hz,
B), 5.18 (d, J = 1.8 Hz, 1 H, CH2, part of an AB system), 5.13 (dd,
J = 51.4, 12.5 Hz, 1 H, CH2, part of an AB system), 4.58 (dd, J =
22.7, 16.5 Hz, 1 H, CH2, part of an AB system), 4.25–4.08 (m, 2
H, CH2), 3.94–3.58 (m, 2 H, CH2), 3.77 (s, 2 H, CH3, A), 3.60 (s,
1 H, CH3, B), 1.43, 1.44 (s, 9 H, tBu, A, B), 1.38–1.11 (m, 2.6 H,
CH2, cPr, A), 0.97–0.80 (m, 1.4 H, CH2, cPr, B) ppm. 13C NMR
(125.7 MHz, CDCl3, APT): δ = 169.9 (–, Cquat, C=O), 169.7 (–,
1 H, NHC=O), 5.12 (s, 2 H, CH2), 3.91 (d, J = 8.7 Hz, 1 H, CH), Cquat, C=O), 168.8 (–, Cquat, C=O), 168.3 (–, Cquat, C=O), 167.9
3.76 (s, 3 H, CH3), 3.30 (d, J = 7.5 Hz, 2 H, CH2N), 1.83 (br. s, 1 (–, 2 Cquat, C=O), 154.8 (–, Cquat, NCOO), 154.1 (–, Cquat, NCOO),
H, NH), 1.44 (s, 9 H, tBu), 0.92–0.67 (m, 4 H, cPr-H) ppm. 13H 135.9 (–, Cquat, Cipso), 135.9 (–, Cquat, Cipso), 128.6 (+, CH, Ph),
NMR (75.5 MHz, CDCl3, APT): δ = 172.2 (–, Cquat, C=O), 171.8
128.6 (+, CH, Ph), 128.3 (+, CH, Ph), 128.1 (+, 2 CH, Ph), 82.2
(–, Cquat, C=O), 156.2 (–, Cquat, NHC=O), 136.3 (–, Cquat, Cipso), (–, Cquat, tBu), 68.0 (–, CH2), 67.8 (–, CH2), 62.8 (+, CH), 62.2 (+,
128.5 (+, 2 CH, Ph), 128.1 (+, CH, Ph), 128.1 (+, 2 CH, Ph), 81.4
(–, Cquat, tBu), 67.0 (–, CH2), 59.2 (+, CH), 52.4 (+, CH3), 48.9
CH), 52.7 (+, OCH3), 52.6 (+, OCH3), 47.5 (–, CH2), 47.4 (–, CH2),
46.0 (–, CH2), 45.7 (–, CH2), 41.4 (–, 2 C, cPr-C), 28.0 (+, CH3,
(–, NHCH2), 41.6 (–, Cquat, cPr-C), 28.0 (+, CH3, tBu), 14.2 (–, tBu), 13.8 (–, CH2, cPr), 13.2 (–, CH2, cPr), 9.9 (–, CH2, cPr), 9.8
CH2, cPr), 12.7 (–, CH2, cPr) ppm. MS (ESI): m/z (%) = 806.8 (18) (–, CH , cPr) ppm. IR (film): ν = 2978 , 1745, 1407, 1367, 1227,
˜
2
[2M + Na]+, 415.1 (100) [M + Na]+. IR (film): ν = 3327 (NH),
3062, 3028, 2929, 1734 (C=O), 1669 (C=O), 1454, 1410, 1347, 1195,
1029, 749, 699 cm–1. C20H28N2O6 (392.45): calcd. C 61.21, H 7.19,
N 7.14; found C 60.92, H 6.98, N 6.93.
1155, 1105, 1016, 748, 699, 662 cm–1. MS (ESI): m/z (%) = 887.1
(100) [2M + Na]+, 455.3 (65) [M + Na]+. C22H28N2O7 (432.47): C
61.10, H. 6.53, N 6.48; found C 61.44, H. 6.19, N 6.12.
˜
Methyl 4-(tert-Butoxycarbonylmethyl)-5-oxo-4,7-diazaspiro[2.5]oc-
Methyl 2-(Benzyloxycarbonylamino)-2-{1-[(2-bromoacetyl)-tert-but- tane-8-carboxylate (15): A solution of 14 (1.36 g, 3.14 mmol) in
oxycarbonylmethylamino]cyclopropyl}acetate (13): To a solution of
12 (2.34 g, 5.96 mmol) in 1,2-dichloroethane (20 mL) was added at
MeOH (50 mL) was added to a pre-hydrogenated suspension of
Pd/C (1.01 g, 10%) in MeOH (20 mL) and the mixture was stirred
20 °C first NaHCO3 (1.60 g, 19.1 mmol) then bromoacetylchloride at 20 °C for 2 h under an atmosphere of hydrogen. Then the sus-
(1.21 g, 7.74 mmol). Water (12 mL) was added dropwise to this vig-
orously stirred mixture, which was kept stirring at 20 °C for 1 h.
The phases were separated, and the aqueous phase was extracted
with CH2Cl2 (2ϫ30 mL). The combined organic phases were dried
pension was filtered through a pad of Celite and the solids were
washed with MeOH (100 mL). Evaporation of the solvents at re-
duced pressure gave 15 (788 mg, 84%) as a colorless viscous oil.
1H NMR (250 MHz, CDCl3, 20 °C): δ = 4.12 (d, J = 8.74 Hz, CH2,
with Na2SO4 and the solvents were removed at reduced pressure. B part of an AB system), 3.75 (s, 3 H, OCH3), 3.68 (d, J = 7.76 Hz,
The residue was purified by column chromatography on silica gel
(hexane/ethyl acetate, 1:1, Rf = 0.18) to afford 2.39 g (78%) of 13
as a colorless oil. 1H NMR (300 MHz, [D6]DMSO, 35 °C) (2 rota-
mers): δ = 7.87 (t, J = 8.3 Hz, 1 H, NH), 7.41–7.29 (m, 5 H, Ph),
5.06 (d, J = 6.8 Hz, 2 H, CH2), 4.53 (d, J = 8.7 Hz, 0.5 H, CH2),
4.35 (d, J = 11.7 Hz, 0.5 H, CH2), 4.12 (d, J = 11.7 Hz, 0.5 H,
CH2), 3.96 (d, J = 8.7 Hz, 0.5 H, CH2), 3.93 (s, 1 H, CH), 3.66 (s,
1 H, CH2, B part of an AB system), 3.61 (d, J = 8.69 Hz, 1 H,
CH2, A part of an ABsystem), 3.58 (d, J = 7.96 Hz, 1 H, CH2, A
part of an AB system), 3.16 (s, 1 H, CH), 2.85–2.61 (br. s, 1 H,
NH), 1.41 (s, 9 H, tBu), 1.30–0.83 (m, 4 H, cPr-H) ppm. 13C NMR
(62.9 MHz, CDCl3, 20 °C, DEPT): δ = 173.0 (Cquat, C=O), 172.7
(Cquat, C=O), 168.1 (Cquat, NC=O), 81.9 (Cquat, tBu), 62.6 (+, CH),
52.6 (+, OCH3), 47.9 (–, CH2), 45.4 (–, CH2), 41.2 (Cquat, cPr-C),
2 H, CH2), 3.26 (s, 3 H, CH3), 1.36 (s, 9 H, tBu), 1.30–1.08 (m, 2 27.8 (+, tBu), 15.2 (–, cPr-C), 8.1 (–, cPr-C) ppm. IR (film): ν =
˜
H, cPr-H), 1.08–0.95 (m, 2 H, cPr-H) ppm. 13C NMR (125.7 MHz,
[D6]DMSO, 35 °C, APT): δ = 170.0 (–, Cquat, C=O), 169.8 (–,
Cquat, C=O), 168.1 (–, 2 Cquat, C=O), 168.0 (–, 2 Cquat, C=O), 156.5
(–, Cquat, C=O), 156.3 (–, Cquat, C=O), 136.6 (–, Cquat, Cipso), 136.5
3311 (NH), 3086, 3060, 3039, 3005, 2985, 2964, 2953, 2932, 2918,
2874, 1733 (C=O), 1663 (C=O), 1469, 1405, 1318, 1208, 1187, 1138,
989, 700 cm–1. MS (ESI): m/z (%) = 597.3 (16) [2M + Na]+, 321.4
(20) [M + Na]+, 299.4 (100) [M + H]+. C14H22N2O5 (298.33): calcd.
(–, Cquat, Cipso), 128.4 (+, 2 CH, Ph), 128.3 (+, 2 CH, Ph), 128.2 C 56.36, H 7.43, N 9.39; found C 56.55, H 7.53, N 9.54.
Eur. J. Org. Chem. 2009, 1357–1364
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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