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B. Jung et al. / Bioorg. Med. Chem. 16 (2008) 2870–2885
ubst. Ar). 1H NMR (CDCl3): d (ppm) = 2.56 (ddd,
J = 19.5/4.3/2.7 Hz, 1H, 4-H), 2.79 (ddd, J = 19.5/4.3/
3.9 Hz, 1H, 4-H), 3.65 (s, 3H, OCH3), 4.02–4.07 (m,
1H, 5-H), 4.31–4.33 (m, 1H, 1-H), 4.33 (d,
J = 14.5 Hz, 1H, CH2PhOCH3), 4.63 (d, J = 14.5 Hz,
1H, CH2PhOCH3), 5.70 (ddd, J = 3.9/2.7/1.2 Hz, 1H,
3-H), 6.57 (d, J = 8.6 Hz, 2H, 30-H and 50-H [H3COPh]),
6.70 (s, 1H, NH), 6.91 (d, J = 8.6 Hz, 2H, 20-H and 60-H
[H3COPh]), 6.95–7.17 (m, 5H, aromat. H).
M, 0.2 mL, 0.2 mmol) and 40 min later a solution of allyl
bromide (0.1 mL, 1.15 mmol) in THF (0.5 mL) were
slowly added. The mixture was stirred for 1 h at ꢀ78 ꢁC
and for 2 h at rt. H2O (30 mL) was added and the mixture
was extracted with CH2Cl2 (3· 50 mL). The organic layer
was dried (Na2SO4), concentrated in vacuo and the resi-
due was purified by fc (1 cm, petroleum ether/ethyl ace-
tate = 3:7, 3 mL, Rf = 0.24). Colorless oil, yield 50.9 mg
(92%). C24H26N2O3 (390.5). [a]589 +135 (c 0.20, CH2Cl2).
MS (ESI): m/z (%) = 803 (2M+Na+, 58), 413 (M+Na+,
+
100), 391 (MH , 8). IR (neat): t [cmꢀ1] = 1670 (s,
~
6.2.34. (+)-(1S,2S,5S)- and (+)-(1S,2R,5S)-8-(-Methoxy-
benzyl)-2-phenyl-6,8-diazabicyclo[3.2.2]nonane-7,9-dione
(27a) and (27b). Under N2 ammonium formate (1.35 g,
26.6 mmol) was added to a suspension of 26 (1.50 g,
3.9 mmol) and 20% Pd/C (0.3 g) in MeOH (150 mL)
and the mixture was heated to reflux for 3 h. Then it
was filtered with Celite, the filtrate was concentrated in
vacuo and the residue was purified by fc (5 cm, ethyl
acetate/acetone = 8:2, 20 mL). The product (colorless
solid, yield 1.31 g, 87%, mixture 27a/27b = 83:17) was
purified once more by fc (4 cm, ethyl acetate, 10 mL).
m
C@Oamide), 1243 (m, mCOC), 1174, 1031 (w, mCOC), 836
(w, p-disubst. Ar), 752, 700 (m, monosubst. Ar). 1H
NMR(CDCl3): d (ppm) = 1.65–1.90 (m, 3H, 3-H, 4-H),
2.03–2.12 (m, 1H, 3-H), 2.36 (dd, J = 11.7/4.7 Hz, 1H,
2-H), 3.73 (s, 3H, OCH3), 3.87 (s, 1H, 1-H), 3.97 (d, J =
7.8 Hz, 1H, 5-H), 4.02–4.06 (m, 2H, NCH2CH@CH2),
4.27 (d, J = 14.6 Hz, 1H, CH2PhOCH3), 4.64 (d,
J = 14.6 Hz, 1H, CH2PhOCH3), 5.17–5.25 (m, 2H,
NCH2CH@CH2), 5.70–5.81 (m, 1H, NCH2CH@CH2),
6.76 (d, J = 8.6 Hz, 2H, 30-H and 50-H [H3COPh]), 6.91
(d, J = 8.6 Hz, 2H, 20-H and 60-H [H3COPh]), 7.07–7.19
(m, 5H, aromat. H).
Compound 27a (Rf = 0.11, ethyl acetate): colorless solid,
mp 196.6 ꢁC, yield 472 mg (35%). C21H22N2O3 (350.5).
Calcd C, 71.9; H, 6.33; N, 7.99. Found: C, 71.7; H,
6.33; N, 7.89. [a]589 +118 (c 0.66, CH2Cl2). MS (ESI):
m/z (%) = 723 (2M+Na+, 52), 373 ( M+Na+, 100). IR
6.2.36. (ꢀ)-(1S,2R,5S)-6-Allyl-8-(4-methoxybenzyl)-2-
phenyl-6,8-diazabicyclo[3.2.2]nonane-7,9-dione (28b). As
described for 28a the diastereomer 27b (60.0 mg,
0.17 mmol) was allylated with NaHMDS (1 M in
THF, 0.2 mL, 0.2 mmol) and allyl bromide (0.2 mL,
2.30 mmol) in the presence of Bu4NI (6.3 mg,
0.017 mmol) in THF (20 mL). After workup the residue
was purified by fc (1 cm, petroleum ether/ethyl acetate =
3:7, 3 mL, Rf = 0.18). Colorless oil, yield 52.7 mg (83%).
C24H26N2O3 (390.5). [a]589 ꢀ6.0 (c 0.29, CH2Cl2). MS
(EI): m/z (%) = 390 (M, 52), 349 (M-allyl, 3), 273
(MH+-allyl-phenyl, 31), 269 ( MꢀCH2PhOCH3, 3),
(neat): t [cmꢀ1] = 3322 (w, mN–H), 1669,1657 (s, mC@Oamide),
~
1511 (m, dN–H), 1243 (s, mCOC), 1168, 1030 (m, mCOC),
802 (m, p-disubst. Ar), 751, 700 (m, monosubst. Ar).
1H NMR(CDCl3): d (ppm) = 1.88–2.18 (m, 4H, 3-H,
4-H), 2.49 (dd, J = 12.1/4.7 Hz, 1H, 2-H), 3.80 (s, 3H,
OCH3), 3.87 (s, 1H, 1-H), 4.10 (dd, J = 7.6/5.5 Hz, 1H,
5-H), 4.42 (d, J = 14.5 Hz, 1H, CH2PhOCH3), 4.67 (d,
J = 14.5 Hz, 1H, CH2PhOCH3), 6.51 (d, J = 5.5 Hz,
1H, NH), 6.84 (d, J = 8.6 Hz, 2H, 30-H and 50-H
[H3COPh]), 7.01 (d, J = 8.6 Hz, 2H, 20-H and 60-H
[H3COPh]), 7.16–7.26 (m, 5H, aromat. H).
121 (CH2PhOCH3, 100). IR (neat): t [cmꢀ1] = 1679 (s,
~
m
C@Oamide), 1246 (m, mCOC), 751 (m, monosubst. Ar).
1H NMR (CDCl3): d (ppm) = 1.73 (dddd, J = 7.0/5.5/
3.1/1.6 Hz, 1H, 4-H), 1.95–2.05 (m, 1H, 3-H), 2.09–
2.18 (m, 1H, 4-H), 2.19–2.26 (m, 1H, 3-H), 3.14 (ddd,
J = 7.8/4.7/1.6 Hz,1H, 2-H), 3.19 (d, J = 14.9 Hz, 1H,
CH2PhOCH3), 3.67 (s, 3H, OCH3), 3.76 (ddd,
J = 14.1/6.3/1.6 Hz, 1H, NCH2CH@CH2), 3.87 (d,
J = 1.6 Hz, 1H, 1-H), 3.93 (dd, J = 5.5/1.6 Hz, 1H, 5-
H), 4.14 (dddd, J = 14.1/6.3/3.1/1.6 Hz, 1H, NCH2
CH@CH2), 4.97 (d, J = 14.9 Hz, 1H, CH2PhOCH3),
4.93–5.24 (m, 2H, NCH2CH@CH2), 5.64–5.75 (m, 1H,
NCH2CH@CH2), 6.63 (d, J = 8.9 Hz, 2H, 30-H and 50-
H [H3COPh]), 6.68 (d, J = 8.9 Hz, 2H, 20-H and 60-H
[H3COPh]), 7.15–7.30 (m, 5H, aromat. H).
Compound 27b (Rf = 0.08, ethyl acetate): colorless solid,
mp 192.1 ꢁC, yield 170 mg (11%). C21H22N2O3 (350.5).
Calcd C, 71.9; H, 6.33; N, 7.99. Found: C, 71.6; H, 6.32;
N, 7.44. [a]589 +71 (c 0.58, CH2Cl2). MS (ESI): m/z
(%) = 1073 (3M+Na+, 100), 723 (2M+Na+, 98), 373
+
+
(M+Na , 4), 351 (MH , 13). IR (neat): t [cmꢀ1] = 3329
~
(w, mN–H), 1675 (s, mC@Oamide), 1512 (m, dN–H), 1245 (s,
m
COC), 1174, 1031 (m, mCOC), 810 (m, p-disubst. Ar), 757,
1
701 (m, monosubst. Ar). H NMR(CDCl3): d (ppm) =
1.77–1.87 (m, 1H, 4-H), 2.11–2.27 (m, 1H, 3-H), 2.18–
2.26 (m, 1H, 4-H), 2.33–2.41 (m, 1H, 3-H), 3.26 (ddd,
J = 9.1/4.3/1.2 Hz, 1H, 2-H), 3.32 (d, J = 14.8 Hz, 1H,
CH2PhOCH3), 3.74 (s, 3H, OCH3), 3.83 (d, J = 1.2 Hz,
1H, 1-H), 4.07 (ddd, J = 7.8/5.1/2.7 Hz, 1H, 5-H), 5.06
(d, J = 14.8 Hz, 1H, CH2PhOCH3), 6.70 (d, J = 8.6 Hz,
2H, 30-H and 50-H [H3COPh]), 6.77 (d, J = 8.6 Hz, 2H,
20-H and 60-H [H3COPh]), 6.88 (d, J = 2.7 Hz, 1H,
NH), 7.20–7.37(m, 5H, aromat. H).
6.2.37.
(ꢀ)-(1S,2S,5S)-6-Allyl-8-(4-methoxybenzyl)-2-
phenyl-6,8-diazabicyclo[3.2.2]nonane (29a). Under N2 a
mixture of LiAlH4 (200 mg, 5.26 mmol) and 28a
(400 mg, 1.02 mmol) in THF (60 mL) was heated to re-
flux for 48 h. Then H2O (0.4 mL) was cautiously added
and the mixture was heated to reflux for 30 min. Then it
was filtered and the filtrate was concentrated in vacuo.
The residue was dissolved in 1 M HCl (30 mL), the solu-
tion was washed with ethyl acetate (2· 20 mL), then 2 M
NaOH (30 mL) was added and the aqueous layer was
extracted with CH2Cl2 (3· 50 mL). The CH2Cl2 layer
6.2.35.
(+)-(1S,2S,5S)-6-Allyl-8-(4-methoxybenzyl)-2-
phenyl-6,8-diazabicyclo[3.2. 2]nonane-7,9-dione (28a).
Under N2 a solution of 27a (50.0 mg, 0.14 mmol) and
Bu4NI (10.5 mg, 0.028 mmol) in THF (20 mL) was cooled
down to ꢀ78 ꢁC. Then a solution of NaHMDS in THF (1