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Wünsch et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 281−290
0.5 N HCl (200 mL), the mixture was extracted with CH2Cl2 (3 ϫ
200 mL), the organic layer was dried (Na2SO4) and concentrated in
vacuo. The residue was purified by flash column chromatography
(8 cm, petroleum ether/ethyl acetate/acetone 3:2:6, 30 mL, Rf ϭ
0.32) to give a colorless solid, yield 6.7 g (88%), mp 93-94°C.
[α]589 ϭ Ϫ14.7, (c 0.51, CH2Cl2). C16H20N2O5 (320.3). Calcd. C
60.0, H 6.29, N 8.74, found C 59.7, H 6.54, N 8.63. MS (EI): m/z
(%) ϭ 320 (M, 11), 288 (M ϪHOCH3, 2), 199 (M Ϫ CH2PhOCH3,
2), 121 (CH2PhOCH3, 100). IR (neat): ν [cmϪ1] 3267 (w, νN-H), 2963
(w, νC-Halip.), 1733 (m, νCϭOester) 1661(s, νCϭOamide), 1534 (w,
δN-Hamide), 1217, 1176 (m, νCOC), 785 (s, p-disubst. ar.). 1H
NMR(CDCl3): δ (ppm) ϭ 2.13Ϫ2.27 (m, 2H, CH2CH2CO2CH3),
2.41Ϫ2.53 (m, 2H, CH2CH2CO2CH3), 3.67 (s, 3H, CO2CH3), 3.78
(d, J ϭ 17.6 Hz, 1H, CH2PhOCH3), 3.79 (s, 3H, OCH3 ), 3.84 (d,
J ϭ 17.6 Hz, 1H, CH2PhOCH3), 4.12 (dd, J ϭ 6.3/3.5 Hz, 1H,
CHNH), 4.51 (s, 2H, OϭC-CH2N), 6.87 (d, J ϭ 8.6 Hz, 2H, 3Ј-H
and 5Ј-H [H3COPh]), 6.98 (s, 1H, NH), 7.18 (d, J ϭ 8.6 Hz, 2H,
2Ј-H and 6Ј-H [H3COPh]).
(CDCl3): δ (ppm) ϭ 0.01 (s, 9H, Si(CH3)3), 1.61Ϫ1.69 (m, 1H, 4-
H), 1.74Ϫ1.81 (m, 2H, 3-H ), 1.87Ϫ1.95 (m, 1H, 4-H) 3.03 (s, 3H,
OCH3), 3.61 (s, 3H, PhOCH3), 3.71 (dd, J ϭ 5.5/2.4 Hz, 1H, 5-H),
3.72 (s, 1H, 1-H), 3.79 (d, J ϭ 14.9 Hz, 1H, CH2PhOCH3), 3.80 (m,
2H, NCH2CHϭCH2), 4.99 (d, J ϭ 14.9 Hz, 1H, CH2PhOCH3),
5.03Ϫ5.07 (m, 2H, NCH2CHϭCH2), 5.52Ϫ5.62 (m, 1H,
NCH2CHϭCH2), 6.68 (d, Jϭ 8.6 Hz, 2H, 3Ј-H and 5Ј-H
[H3COPh]), 6.96 (d, J ϭ 8.6 Hz, 2H, 2Ј-H and 6Ј-H [H3COPh]).
13C NMR (CDCl3): δ (ppm) ϭ 24.7 (1C, C-4), 33.3 (1C, C-3), 47.6
(1C, NCH2CHϭCH2), 48.0 (1C, CH2PhOCH3), 49.0 (1C, OCH3),
55.2 (1C, PhOCH3), 58.3 (1C, C-5), 65.8 (1C, C-1), 98.6 (1C, C-2),
114.2 (2C, C-3Ј and C-5Ј[H3COPh]), 119.0 (1C, NCH2CHϭCH2),
127.9 (1C, C-1Ј[H3COPh]), 129.4 (2C, C-2Ј and C-6Ј [H3COPh]),
132.2 (1C, NCH2CHϭCH2), 159.2 (1C, C-4Ј [H3COPh]), 165.8 (1C,
CϭO), 168.6 (1C, CϭO).
(1S,5S)-6-Allyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]-
nonane-2,7,9-trione (17)
Under N2 atmosphere a solution of 20 (1.12 g, 2.59 mmol) was
stirred at room temperature in a degassed mixture of THF/2 N HCl
(10:1, 50 mL) for 2 h. Subsequently, water (50 mL) was added and
the mixture was extracted with CH2Cl2 (3 ϫ 50 mL). The organic
layer was dried (Na2SO4) and the solvent was removed in vacuo.
Methyl (S)-3-[5-allyl-4-(4-methoxybenzyl)-3,6-dioxopiperazin-2-yl]-
propanoate (18)
Under N2 atmosphere a solution of phenylmagnesium bromide pre-
pared from bromobenzene (0.064 mL, 0.61 mmol) and magnesium
tunings (0.015 g, 0.61 mmol) in THF (2 mL) was added to a cooled
(Ϫ78°C) solution of 14 (0.20 g, 0.55 mmol) in THF (20 mL). After
stirring at Ϫ78°C for 2 h and at room temperature for 1 h the
mixture was poured into an ice cooled saturated solution of NH4Cl
(30 mL). The mixture was extracted four times with CH2Cl2, the
organic layer was dried, the solvent was removed in vacuo and the
residue was purified by flash column chromatography (2 cm,
CH2Cl2 /ethyl acetate 7:3, 5 mL) to give 17 (Rf ϭ 0.31) as a colorless
solid, yield 18.8 mg (10%) and 18 (Rf ϭ 0.18) as a pale yellow oil,
yield 29.3 mg, (15%). 18: C19H22N2O5 (360.4). MS (ESI): m/z (%) ϭ
383 (M ϩ Naϩ, 100). IR (neat): ν [cmϪ1] ϭ 3233 (w, νN-H), 2951
(w, μnC-Haliph.), 1734 (m, νCϭOester), 1681 (m, νCϭOsec.amide), 1654
(m, νCϭOtert.amide), 1512 (m, δN-H),1245, 1174 (m, νCOC), 807 (w,
p-disubst. ar.). 1H NMR (CDCl3): δ (ppm) ϭ 2.13Ϫ2.38 (m, 2H,
CH2CH2CO2CH3), 2.33Ϫ2.45 (m, 2H, CH2CH2CO2CH3),
2.49Ϫ2.58 (m, 2H, CH2CHϭCH2), 3.60 (s, 3H, CO2CH3), 3.73 (s,
3H, OCH3), 3.83 (m, 1H, OϭC-CHN), 3.86 (d, J ϭ 14.5 Hz, 1H,
CH2PhOCH3), 4.14 (t, J ϭ 4.7 Hz, 1H, CHNH), 5.10 (m, 2H,
CH2CHϭCH2), 5.21 (d, J ϭ 14.5Hz, 1H, CH2PhOCH3), 5.62Ϫ5.74
(m, 1H, CH2CHϭCH2), 6.50 (s, 1H, NH), 6.80 (d, J ϭ 8.6 Hz, 2H,
3Ј-H and 5Ј-H [H3COPh]), 7.10 (d, J ϭ 8.6 Hz, 2H, 2Ј-H and
6Ј-H [H3COPh]).
Colorless solid, yield 0.85 g (100%), mp 195-196°C. [α]589
ϭ
ϩ120.29 (c 0.49, CH2Cl2). C18H20N2O4 (328.4). Calcd. C 65.8, H
6.14, N 8.53, found C 65.6, H 5.95, N 8.25. MS (EI): m/z (%) ϭ
329 (M, 100), 121 (CH2PhOCH3, 12). IR (neat): ν [cmϪ1] ϭ 3005
(w, νC-Harom.), 2955 (w, νC-Haliph.), 1724 (s, νCϭOketone), 1670 (s,
νCϭOamide), 1243, (m, νCOC), 828 (s, p-disubst. ar.).1H NMR
(CDCl3): δ (ppm) ϭ 1.99Ϫ2.13 (m, 1H, 4-H), 2.21Ϫ2.32 (m, 1H,
3-H ), 2.35Ϫ2.48 (m, 2H, 3ϪH, 4-H), 3.71 (s, 3H, PhOCH3), 3.81
(ddt, J ϭ 17.9/6.3/1.6 Hz, 1H, NCH2CHϭCH2), 3.99 (dd, 1H, J ϭ
6.3/1.6 Hz, 1H, 5-H), 4.11 (ddt,
J ϭ 17.9/6.3/1.6 Hz, 1H,
NCH2CHϭCH2), 4.20 (s, 1H, 1-H), 4.26 (d, J ϭ 14.1 Hz, 1H,
CH2PhOCH3), 4.76 (d, J ϭ 14.1 Hz, 1H, CH2PhOCH3) 5.16Ϫ5.24
(m, 2H, NCH2CHϭCH2 ), 5.61Ϫ5.73 (m, 1H, NCH2CHϭCH2),
6.76 (d, J ϭ 8.6 Hz, 2H, 3Ј-H and 5Ј-H [H3COPh]), 7.14 (d, J ϭ
8.6 Hz, 2H, 2Ј-H and 6Ј-H [H3COPh]). 13C NMR (CDCl3): δ
(ppm) ϭ 30.2 (1C, C-4), 36.9 (1C, C-3), 48.1 (1C, NCH2CHϭCH2),
49.4 (1C, CH2PhOCH3), 55.8 (1C, OCH3), 59.0 (1C, C-5), 72.1 (1C,
C-1), 114.7 (2C, C-3Ј and C-5Ј[H3COPh]), 120.2 (1C, NCH2CHϭ
CH2), 127.0 (1C, C-1Ј[H3COPh]), 130.5 (2C, C-2Ј and C-6Ј
[H3COPh]), 131.6 (1C, NCH2CHϭCH2), 159.7 (1C, C-
4Ј[H3COPh]), 163.2 (1C, CϭO), 167.1 (1C, CϭO), 200.2 (1C, Cϭ
Oketone).
(1S,2R,5S)-6-Allyl-2-methoxy-8-(4-methoxybenzyl)-2-(trimethyl-
(1S,2S,5S)-6-Allyl-2-hydroxy-8-(4-methoxybenzyl)-2-phenyl-6,8-
siloxy)-6,8-diazabicyclo[3.2.2]nonane-7,9-dione (20)
diazabicyclo[3.2.2]- nonane-7,9-dione (21)
Under N2 atmosphere a 1 M solution of lithium hexamethyldi-
silazane in THF (13.5 mL, 13.5 mmol) was added dropwise to a
cooled solution (Ϫ78°C) of 14 (3.25 g, 9.02 mmol) in THF
(130 mL). After stirring at Ϫ78°C for 40 min, a solution of chloro-
trimethylsilane (4.1 mL, 32.5 mmol) in THF (10 mL) was added.
The mixture was stirred at Ϫ78°C for 1 h and at room temperature
for 2 h. Then a saturated solution of sodium hydrogen carbonate
(150 mL) was added and the mixture was extracted with CH2Cl2
(3 ϫ 150 mL). The organic layer was dried (Na2SO4), the solvent
was removed in vacuo and the residue was purified by flash column
chromatography (6 cm, petroleum ether/ethyl acetate 6:4, 30 mL,
Rf ϭ 0.27) to give a colorless solid, yield 3.4 g (88%), mp 93Ϫ94°C.
[α]589 ϭ ϩ22.07, (c 0.995, CH2Cl2). C22H32N2O5Si (432.6). Calcd.
C 61.1, H 7.46, N 6.48, found C 60.6, H 7.30, N 6.38. MS (EI): m/z
Under N2 atmosphere a solution of 17 (2.2 g, 6.7 mmol) in THF
(100 mL) was added to an ice-cooled solution of phenylmagnesium
bromide prepared from bromobenzene (4.2 mL, 40.0 mmol) and
magnesium tunings (1.0 g, 40.7 mmol) in THF (10 mL). After stir-
ring for 2 h at 0Ϫ5°C the mixture was poured into a cold saturated
solution of NH4Cl (200 mL). The mixture was extracted four times
with CH2Cl2 (150 mL), the organic layer was dried, the solvent was
removed in vacuo and the residue was purified by flash column chro-
matography (4 cm, petroleum ether/ethyl acetate 2:8, 20 mL, Rf ϭ
0.25) to give a yellow oil, yield 2.5 g (90%). [α]589 ϭ ϩ3.96, (c 1.0,
CH2Cl2). C24H26N2O4 (406.5). MS (EI): m/z (%) ϭ 406 (M, 25),
365 (M-allyl, 10), 285 (M-CH2PhOCH3), 121 (CH2PhOCH3, 100).
IR (neat): ν [cmϪ1] ϭ 3400 (w, νO-H), 2935 (w, νC-Haliph.),1664 (s,
νCϭOamide), 1244 (s, νCOC), 809 (w, p-disubst. ar.), 753 (m, mono-
subst. ar), 701 (s, monosubst. ar). 1H NMR (CDCl3): δ (ppm) ϭ
1.94Ϫ2.07 (m, 1H, 3-H), 2.13Ϫ2.21 (m, 2H, 4-H ), 2.48Ϫ2.60 (m,
1H, 3ϪH), 2.82 (d, J ϭ 14.7 Hz, 1H, CH2PhOCH3), 3.37 (s, 1H,
(%)
ϭ 432 (M, 33), 311 (M Ϫ CH2PhOCH3, 24), 121
(CH2PhOCH3, 100). IR (neat): ν [cm1] ϭ 2954 (w, νC-Halip.), 1679
(s, νCϭOamide), 1251 (s, νCOC), 832 (s, p-disubst. ar.). 1H NMR
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